Safe and Effective Method of Treating Psoriatic Arthritis with Anti-IL23 Specific Antibody

ABSTRACT

A method of treating psoriatic arthritis in a patient by administering an IL-23 specific antibody, e.g., guselkumab, in a clinically proven safe and clinically proven effective amount and the patient achieves significant ACR20/50/70, PASI70/90/100, MDA, HAQ-DI, SF-36 PCS, MCS, LEI/dactylitis, PASDAS, GRACE, mCPDAI, DAPSA or RAPID3 improvement as measured 16, 24, 32, 40 and 48 weeks after initial treatment.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 62/581,996, filed 6 Nov. 2017, and U.S. Provisional Application Ser.No. 62/744,386, filed 11 Oct. 2018. The entire contents of theaforementioned applications are incorporated herein by reference intheir entireties.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on 5 Nov. 2018, isnamed JBI5144USNP1SEQLIST.txt and is 79,736 bytes in size.

FIELD OF THE INVENTION

The present invention concerns methods for treating psoriatic arthritiswith an antibody that binds the human IL-23 protein. In particular, itrelates to a method of administering an anti-IL-23 specific antibody andspecific pharmaceutical compositions of an antibody, e.g., guselkumab,which is safe and effective for patients suffering from psoriaticarthritis.

BACKGROUND OF THE INVENTION

Interleukin (IL)-12 is a secreted heterodimeric cytokine comprised of 2disulfide-linked glycosylated protein subunits, designated p35 and p40for their approximate molecular weights. IL-12 is produced primarily byantigen-presenting cells and drives cell-mediated immunity by binding toa two-chain receptor complex that is expressed on the surface of T cellsor natural killer (NK) cells. The IL-12 receptor beta-1 (IL-12Rβ1) chainbinds to the p40 subunit of IL-12, providing the primary interactionbetween IL-12 and its receptor. However, it is IL-12p35 ligation of thesecond receptor chain, IL-12Rβ2, that confers intracellular signaling(e.g. STAT4 phosphorylation) and activation of the receptor-bearingcell. IL-12 signaling concurrent with antigen presentation is thought toinvoke T cell differentiation towards the T helper 1 (Th1) phenotype,characterized by interferon gamma (IFNγ) production. Th1 cells arebelieved to promote immunity to some intracellular pathogens, generatecomplement-fixing antibody isotypes, and contribute to tumorimmunosurveillance. Thus, IL-12 is thought to be a significant componentto host defense immune mechanisms.

It was discovered that the p40 protein subunit of IL-12 can alsoassociate with a separate protein subunit, designated p19, to form anovel cytokine, IL-23. IL-23 also signals through a two-chain receptorcomplex. Since the p40 subunit is shared between IL-12 and IL-23, itfollows that the IL-12Rβ1 chain is also shared between IL-12 and IL-23.However, it is the IL-23p19 ligation of the second component of theIL-23 receptor complex, IL-23R, that confers IL-23 specificintracellular signaling (e.g., STAT3 phosphorylation) and subsequentIL-17 production by T cells. Recent studies have demonstrated that thebiological functions of IL-23 are distinct from those of IL-12, despitethe structural similarity between the two cytokines.

Abnormal regulation of IL-12 and Th1 cell populations has beenassociated with many immune-mediated diseases since neutralization ofIL-12 by antibodies is effective in treating animal models of psoriasis,multiple sclerosis (MS), rheumatoid arthritis, inflammatory boweldisease, insulin-dependent (type 1) diabetes mellitus, and uveitis.However, since these studies targeted the shared p40 subunit, both IL-12and IL-23 were neutralized in vivo. Therefore, it was unclear whetherIL-12 or IL-23 was mediating disease, or if both cytokines needed to beinhibited to achieve disease suppression. Studies have confirmed throughIL-23p19 deficient mice or specific antibody neutralization of IL-23that IL-23 inhibition can provide equivalent benefit as anti-IL-12p40strategies. Therefore, there is increasing evidence for the specificrole of IL-23 in immune-mediated disease. Neutralization of IL-23without inhibition of IL-12 pathways could then provide effectivetherapy of immune-mediated disease with limited impact on important hostdefense immune mechanism. This would represent a significant improvementover current therapeutic options.

Psoriasis is a common, chronic immune-mediated skin disorder withsignificant co-morbidities, such as psoriatic arthritis (PsA),depression, cardiovascular disease, hypertension, obesity, diabetes,metabolic syndrome, and Crohn's disease. Plaque psoriasis is the mostcommon form of the disease and manifests in well demarcated erythematouslesions topped with white silver scales. Plaques are pruritic, painful,often disfiguring and disabling, and a significant proportion ofpsoriatic patients have plaques on hands/nails face, feet and genitalia.As such, psoriasis negatively impacts health-related quality of life(HRQoL) to a significant extent, including imposing physical andpsychosocial burdens that extend beyond the physical dermatologicalsymptoms and interfere with everyday activities. For example, psoriasisnegatively impacts familial, spousal, social, and work relationships,and is associated with a higher incidence of depression and increasedsuicidal tendencies.

Psoriatic arthritis (PsA) is a multi-system disease characterized byjoint inflammation and psoriasis, with diverse clinical and radiographicmanifestations including dactylitis, enthesitis, sacroiliitis, and/orjoint deformity. Functional impairment, decreased quality of life, andincreased health-care resource utilization associated withpoorly-controlled PsA present significant economic burden. Despiteavailability of biologics (e.g., tumor-necrosis-factor [TNF]αinhibitors, ustekinumab, secukinumab), and other agents (e.g.,apremilast), significant unmet needs exist for new PsA therapies thatcan provide high levels of efficacy and safety in treating heterogeneousdisease components

Histologic characterization of psoriasis lesions reveals a thickenedepidermis resulting from aberrant keratinocyte proliferation anddifferentiation as well as dermal infiltration and co-localization ofCD3+T lymphocytes and dendritic cells. While the etiology of psoriasisis not well defined, gene and protein analysis have shown that IL-12,IL-23 and their downstream molecules are over-expressed in psoriaticlesions, and some may correlate with psoriasis disease severity. Sometherapies used in the treatment of psoriasis modulate IL-12 and IL-23levels, which is speculated to contribute to their efficacy. Th1 andTh17 cells can produce effector cytokines that induce the production ofvasodilators, chemoattractants and expression of adhesion molecules onendothelial cells which in turn, promote monocyte and neutrophilrecruitment, T cell infiltration, neovascularization and keratinocyteactivation and hyperplasia. Activated keratinocytes can producechemoattractant factors that promote neutrophil, monocyte, T cell, anddendritic cell trafficking, thus establishing a cycle of inflammationand keratinocyte hyperproliferation.

Elucidation of the pathogenesis of psoriasis has led to effectivebiologic treatments targeting tumor necrosis factor-alpha (TNF-α), bothinterleukin (IL)-12 and IL-23 and, most recently, IL-17 as well as IL-23alone (including in Phase 1 and 2 clinical trials using guselkumab).Guselkumab (also known as CNTO 1959) is a fully human IgG1 lambdamonoclonal antibody that binds to the p19 subunit of IL-23 and inhibitsthe intracellular and downstream signaling of IL-23, required forterminal differentiation of T helper (Th)17 cells. Biologics targetingIL-12/23 or the downstream IL-17 or IL-17R (e.g., ustekinumab,secukinumab, ixekizumab, brodalumab) have consistently demonstratedrobust efficacy in phase-2/3 psoriasis/PsA trials.

SUMMARY OF THE INVENTION

In a first aspect, the invention concerns a method of treatingpsoriastic arthritis in a patient comprising subcutaneouslyadministering an anti-IL-23 specific antibody (also referred to asIL-23p19 antibody), e.g., guselkumab, to the patient, wherein theanti-IL-23 specific antibody is administered at an initial dose, a dose4 weeks thereafter, and at a dosing interval of once every 8 weeksthereafter, e,g., a dose at 0, 4, 8, 16, 24, 32, 40 and 48 weeks.

In another aspect, the composition used in the method of the inventioncomprises a pharmaceutical composition comprising: an anti-IL-23specific antibody in an amount from about 1.0 μg/ml to about 1000 mg/ml,specifically at 50 mg or 100 mg. In a preferred embodiment, theanti-IL-23 specific antibody is guselkumab at 100 mg/mL; 7.9% (w/v)sucrose, 4.0 mM Histidine, 6.9 mM L-Histidine monohydrochloridemonohydrate; 0.053% (w/v) Polysorbate 80 of the pharmaceuticalcomposition; wherein the diluent is water at standard state.

In an embodiment of the method of the invention, PsA patients achievedsignificant improvement in ACR20 response for guselkumab vs. placebo byweek 24 (58% vs 18.4% of guselkumab vs. placebo-treated patients) andconsistently higher ACR50 and ACR70 responses over time through week 24.

In another aspect of the invention, the pharmaceutical compositioncomprises an isolated anti-IL23 specific antibody having the guselkumabCDR sequences comprising (i) the heavy chain CDR amino acid sequences ofSEQ ID NO: 5, SEQ ID NO: 20, and SEQ ID NO: 44; and (ii) the light chainCDR amino acid sequences of SEQ ID NO: 50, SEQ ID NO: 56, and SEQ ID NO:73 at 100 mg/mL; 7.9% (w/v) sucrose, 4.0 mM Histidine, 6.9 mML-Histidine monohydrochloride monohydrate; 0.053% (w/v) Polysorbate 80of the pharmaceutical composition; wherein the diluent is water atstandard state.

Another aspect of the method of the invention comprises administering apharmaceutical composition comprising an isolated anti-IL-23 specificantibody having the guselkumab heavy chain variable region amino acidsequence of SEQ ID NO: 106 and the guselkumab light chain variableregion amino acid sequence of SEQ ID NO: 116 at 100 mg/mL; 7.9% (w/v)sucrose, 4.0 mM Histidine, 6.9 mM L-Histidine monohydrochloridemonohydrate; 0.053% (w/v) Polysorbate 80 of the pharmaceuticalcomposition; wherein the diluent is water at standard state.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Shows a Shematic Overview of the Trial Study. Note that onepatient who completed 44 weeks of treatment with the study drug was lostto follow-up and did not attend the week 56 follow-up visist.

FIGS. 2A-D. Show the proportions of patients achieving ACR20 (2A), ACR50(2B), ACR70 (2C), and Minimal Disease Activity, MDA (2D) responses overtime, in the modified intention-to-treat (mITT/FAS) population using NRIfor treatment-failures, early-escape, and missing data. P values derivedfrom CMH testing. P values for ACR50 (other than Week24), ACR70 and MDAat Week16 were calculated post-hoc. ACR20/50/70—American College ofRheumatology 20/50/70% improvement=proportion of patients with at least20%, 50%, and 70% improvement in signs or symptoms of psoriaticarthritis, according to ACR criteria., CMH—Cochran-Mantel-Haenszel,MDA—minimal disease activity, FAS—full analyses set, mITT—modifiedintent-to-treat.

FIGS. 3A-J. Show proportions of patients achieving MDA (3A) and VLDA(3B) at Week 16 and Week 24 (full analysis set; NRI) and proportions ofpatients achieving disease activity states, and mean changes frombaseline at Week 16 and Week 24 for PASDAS (3C, 3D), GRACE (3E, 3F),mCPDAI (3G, 3H), and DAPSA (3I, 3J) PsA-specific composite endpoints(full analysis set; last observation carried forward for missing data).DAPSA=Disease Activity Index for PSoriatic Arthritis, GRACE=Group forResearch and Assessment of Psoriasis and Psoriatic Arthritis (GRAppa)Composite scorE, mCPDAI=modified Composite Psoriatic Disease ActivityIndex, MDA=minimal disease activity, NRI=nonresponder imputation,PASDAS—Psoriatic ArthritiS Disease Activity Score, PsA=psoriaticarthritis, VLDA=very low disease activity.

FIGS. 4A-D. Show mean changes from baseline at Week 24 in the SF-36 PCSscore by disease activity state according to the PASDAS (4A), GRACE(4B), mCPDAI (4C), and DAPSA (4D) PsA-specific composite endpoints(guselkumab-treated patients in the full analysis set; last observationcarried forward for missing data). DAPSA=Disease Activity Index forPSoriatic Arthritis, GRACE=Group for Research and Assessment ofPsoriasis and Psoriatic Arthritis (GRAppa) Composite scorE,mCPDAI=modified Composite Psoriatic Disease Activity Index,PASDAS=Psoriatic ArthritiS Disease Activity Score, PCS=physicalcomponent summary, PsA=psoriatic arthritis, SF-36=36-item Short Formhealth survey.

FIGS. 5A-J. Show proportions of patients achieving MDA (5A) and VLDA(5B) and proportions of patients achieving disease activity states, andmean changes from baseline, post-Week 24 for PASDAS (5C, 5D), GRACE (5E,5F), mCPDAI (5G, 5H), and DAPSA (5I, 5J) PsA-specific compositeendpoints (post-Week 24 efficacy analysis set; observed data). Week-24observed data in the same population included as a reference.DAPSA=Disease Activity Index for PSoriatic Arthritis, GRACE=Group forResearch and Assessment of Psoriasis and Psoriatic Arthritis (GRAppa)Composite scorE, mCPDAI=modified Composite Psoriatic Disease ActivityIndex, MDA=minimal disease activity, PASDAS—Psoriatic ArthritiS DiseaseActivity Score, PsA=psoriatic arthritis, VLDA=very low disease activity.

FIGS. 6A-C. Show comparative statistics evaluating guselkumab treatmenteffects detected at Week 24 according to the PASDAS, GRACE, mCPDAI, andDAPSA PsA-specific composite endpoints: standardized mean difference(6A), effect size (6B), and standardized response mean (6C) (fullanalysis set; last observation carried forward for missing data).CI=confidence interval, DAPSA=Disease Activity Index for PSoriaticArthritis, GRACE=Group for Research and Assessment of Psoriasis andPsoriatic Arthritis (GRAppa) Composite scorE, mCPDAI=modified CompositePsoriatic Disease Activity Index, PASDAS=Psoriatic ArthritiS DiseaseActivity Score, PsA=psoriatic arthritis.

FIGS. 7A and 7B. Show proportion of patients with dactylitis resolutionover time.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As used herein the method of treatment of psoriasis comprisesadministering isolated, recombinant and/or synthetic anti-IL-23 specifichuman antibodies and diagnostic and therapeutic compositions, methodsand devices.

As used herein, an “anti-IL-23 specific antibody,” “anti-IL-23antibody,” “antibody portion,” or “antibody fragment” and/or “antibodyvariant” and the like include any protein or peptide containing moleculethat comprises at least a portion of an immunoglobulin molecule, such asbut not limited to, at least one complementarity determining region(CDR) of a heavy or light chain or a ligand binding portion thereof, aheavy chain or light chain variable region, a heavy chain or light chainconstant region, a framework region, or any portion thereof, or at leastone portion of an IL-23 receptor or binding protein, which can beincorporated into an antibody of the present invention. Such antibodyoptionally further affects a specific ligand, such as but not limitedto, where such antibody modulates, decreases, increases, antagonizes,agonizes, mitigates, alleviates, blocks, inhibits, abrogates and/orinterferes with at least one IL-23 activity or binding, or with IL-23receptor activity or binding, in vitro, in situ and/or in vivo. As anon-limiting example, a suitable anti-IL-23 antibody, specified portionor variant of the present invention can bind at least one IL-23molecule, or specified portions, variants or domains thereof. A suitableanti-IL-23 antibody, specified portion, or variant can also optionallyaffect at least one of IL-23 activity or function, such as but notlimited to, RNA, DNA or protein synthesis, IL-23 release, IL-23 receptorsignaling, membrane IL-23 cleavage, IL-23 activity, IL-23 productionand/or synthesis.

The term “antibody” is further intended to encompass antibodies,digestion fragments, specified portions and variants thereof, includingantibody mimetics or comprising portions of antibodies that mimic thestructure and/or function of an antibody or specified fragment orportion thereof, including single chain antibodies and fragmentsthereof. Functional fragments include antigen-binding fragments thatbind to a mammalian IL-23. For example, antibody fragments capable ofbinding to IL-23 or portions thereof, including, but not limited to, Fab(e.g., by papain digestion), Fab′ (e.g., by pepsin digestion and partialreduction) and F(ab′)2 (e.g., by pepsin digestion), facb (e.g., byplasmin digestion), pFc′ (e.g., by pepsin or plasmin digestion), Fd(e.g., by pepsin digestion, partial reduction and reaggregation), Fv orscFv (e.g., by molecular biology techniques) fragments, are encompassedby the invention (see, e.g., Colligan, Immunology, supra).

Such fragments can be produced by enzymatic cleavage, synthetic orrecombinant techniques, as known in the art and/or as described herein.Antibodies can also be produced in a variety of truncated forms usingantibody genes in which one or more stop codons have been introducedupstream of the natural stop site. For example, a combination geneencoding a F(ab′)₂ heavy chain portion can be designed to include DNAsequences encoding the C_(H)1 domain and/or hinge region of the heavychain. The various portions of antibodies can be joined togetherchemically by conventional techniques or can be prepared as a contiguousprotein using genetic engineering techniques.

As used herein, the term “human antibody” refers to an antibody in whichsubstantially every part of the protein (e.g., CDR, framework, C_(L),C_(H) domains (e.g., C_(H)1, C_(H)2, C_(H)3), hinge, (V_(L), V_(H))) issubstantially non-immunogenic in humans, with only minor sequencechanges or variations. A “human antibody” may also be an antibody thatis derived from or closely matches human germline immunoglobulinsequences. Human antibodies may include amino acid residues not encodedby germline immunoglobulin sequences (e.g., mutations introduced byrandom or site-specific mutagenesis in vitro or by somatic mutation invivo). Often, this means that the human antibody is substantiallynon-immunogenic in humans. Human antibodies have been classified intogroupings based on their amino acid sequence similarities. Accordingly,using a sequence similarity search, an antibody with a similar linearsequence can be chosen as a template to create a human antibody.Similarly, antibodies designated primate (monkey, baboon, chimpanzee,etc.), rodent (mouse, rat, rabbit, guinea pig, hamster, and the like)and other mammals designate such species, sub-genus, genus, sub-family,and family specific antibodies. Further, chimeric antibodies can includeany combination of the above. Such changes or variations optionally andpreferably retain or reduce the immunogenicity in humans or otherspecies relative to non-modified antibodies. Thus, a human antibody isdistinct from a chimeric or humanized antibody.

It is pointed out that a human antibody can be produced by a non-humananimal or prokaryotic or eukaryotic cell that is capable of expressingfunctionally rearranged human immunoglobulin (e.g., heavy chain and/orlight chain) genes. Further, when a human antibody is a single chainantibody, it can comprise a linker peptide that is not found in nativehuman antibodies. For example, an Fv can comprise a linker peptide, suchas two to about eight glycine or other amino acid residues, whichconnects the variable region of the heavy chain and the variable regionof the light chain. Such linker peptides are considered to be of humanorigin.

Bispecific, heterospecific, heteroconjugate or similar antibodies canalso be used that are monoclonal, preferably, human or humanized,antibodies that have binding specificities for at least two differentantigens. In the present case, one of the binding specificities is forat least one IL-23 protein, the other one is for any other antigen.Methods for making bispecific antibodies are known in the art.Traditionally, the recombinant production of bispecific antibodies isbased on the co-expression of two immunoglobulin heavy chain-light chainpairs, where the two heavy chains have different specificities (Milsteinand Cuello, Nature 305:537 (1983)). Because of the random assortment ofimmunoglobulin heavy and light chains, these hybridomas (quadromas)produce a potential mixture of 10 different antibody molecules, of whichonly one has the correct bispecific structure. The purification of thecorrect molecule, which is usually done by affinity chromatographysteps, is rather cumbersome, and the product yields are low. Similarprocedures are disclosed, e.g., in WO 93/08829, U.S. Pat. Nos.6,210,668, 6,193,967, 6,132,992, 6,106,833, 6,060,285, 6,037,453,6,010,902, 5,989,530, 5,959,084, 5,959,083, 5,932,448, 5,833,985,5,821,333, 5,807,706, 5,643,759, 5,601,819, 5,582,996, 5,496,549,4,676,980, WO 91/00360, WO 92/00373, EP 03089, Traunecker et al., EMBOJ. 10:3655 (1991), Suresh et al., Methods in Enzymology 121:210 (1986),each entirely incorporated herein by reference.

Anti-IL-23 specific (also termed IL-23 specific antibodies) (orantibodies to IL-23) useful in the methods and compositions of thepresent invention can optionally be characterized by high affinitybinding to IL-23 and, optionally and preferably, having low toxicity. Inparticular, an antibody, specified fragment or variant of the invention,where the individual components, such as the variable region, constantregion and framework, individually and/or collectively, optionally andpreferably possess low immunogenicity, is useful in the presentinvention. The antibodies that can be used in the invention areoptionally characterized by their ability to treat patients for extendedperiods with measurable alleviation of symptoms and low and/oracceptable toxicity. Low or acceptable immunogenicity and/or highaffinity, as well as other suitable properties, can contribute to thetherapeutic results achieved. “Low immunogenicity” is defined herein asraising significant HAHA, HACA or HAMA responses in less than about 75%,or preferably less than about 50% of the patients treated and/or raisinglow titres in the patient treated (less than about 300, preferably lessthan about 100 measured with a double antigen enzyme immunoassay)(Elliott et al., Lancet 344:1125-1127 (1994), entirely incorporatedherein by reference). “Low immunogenicity” can also be defined as theincidence of titrable levels of antibodies to the anti-IL-23 antibody inpatients treated with anti-IL-23 antibody as occurring in less than 25%of patients treated, preferably, in less than 10% of patients treatedwith the recommended dose for the recommended course of therapy duringthe treatment period.

The terms “clinically proven efficacy” and “clinically proven effective”as used herein in the context of a dose, dosage regimen, treatment ormethod refer to the clinically proven effectiveness of a particulardose, dosage or treatment regimen. Efficacy can be measured based onchange in the course of the disease in response to an agent of thepresent invention based on the clinical trials conducted, e.g., Phase 2clinical trials and earlier. For example, an anti-IL-23 antibody of thepresent invention (e.g., the anti-IL-23 antibody guselkumab) isadministered to a patient in an amount and for a time sufficient toinduce an improvement, preferably a sustained improvement, in at leastone indicator that reflects the severity of the disorder that is beingtreated. Various indicators that reflect the extent of the subject'sillness, disease or condition may be assessed for determining whetherthe amount and time of the treatment is sufficient. Such indicatorsinclude, for example, clinically recognized indicators of diseaseseverity, symptoms, or manifestations of the disorder in question. Thedegree of improvement generally is determined by a physician, who maymake this determination based on signs, symptoms, biopsies, or othertest results, and who may also employ questionnaires that areadministered to the subject, such as quality-of-life questionnairesdeveloped for a given disease. For example, an anti-IL-23 antibody ofthe present invention may be administered to achieve an improvement in apatient's condition related to psoriatic arthritis. Improvement may beindicated by an improvement in an index of disease activity, byamelioration of clinical symptoms or by any other measure of diseaseactivity. One such index of disease is the ACR 20% improvement criteria(ACR20). Also, the Psoriasis Area and Severity Index (PAST) is an indexof disease used to assess skin disease severity/extent, e.g., PASI75=75%improvement, PASI90=90% improvement and PASI100=substantially cleared ofplaques. The measure of efficacy can also comprise HAQ-DI,enthesitis/dactylitis improvements in patients with baselineenthesitis/dactylitis, changes in SF-36 mental and physical componentsummary (MCS and PCS) scores, and achievement of minimal diseaseactivity (MDA) criteria score.

The term “clinically proven safe,” as it relates to a dose, dosageregimen, treatment or method with an anti-IL-23 antibody of the presentinvention (e.g., the anti-IL-23 antibody guselkumab), refers to arelatively low or reduced frequency and/or low or reduced severity oftreatment-emergent adverse events (referred to as AEs or TEAEs) from theclinical trials conducted, e.g., Phase 2 clinical trials and earlier,compared to the standard of care or to another comparator. An adverseevent is an untoward medical occurrence in a patient administered amedicinal product. In particular, clinically proven safe as it relatesto a dose, dosage regimen or treatment with an anti-IL-23 antibody ofthe present invention refers to a relatively low or reduced frequencyand/or low or reduced severity of adverse events associated withadministration of the antibody if attribution is considered to bepossible, probable, or very likely due to the use of the anti-IL-23antibody.

As used herein, unless otherwise noted, the term “clinically proven”(used independently or to modify the terms “safe” and/or “effective”)shall mean that it has been proven by a clinical trial wherein theclinical trial has met the approval standards of U.S. Food and DrugAdministration, EMEA or a corresponding national regulatory agency. Forexample, the clinical study may be an adequately sized, randomized,double-blinded study used to clinically prove the effects of the drug.

Utility

The isolated nucleic acids of the present invention can be used forproduction of at least one anti-IL-23 antibody or specified variantthereof, which can be used to measure or effect in a cell, tissue, organor animal (including mammals and humans), to diagnose, monitor,modulate, treat, alleviate, help prevent the incidence of, or reduce thesymptoms of psoriasis.

Such a method can comprise administering an effective amount of acomposition or a pharmaceutical composition comprising at least oneanti-IL-23 antibody to a cell, tissue, organ, animal or patient in needof such modulation, treatment, alleviation, prevention, or reduction insymptoms, effects or mechanisms. The effective amount can comprise anamount of about 0.001 to 500 mg/kg per single (e.g., bolus), multiple orcontinuous administration, or to achieve a serum concentration of0.01-5000 μg/ml serum concentration per single, multiple, or continuousadministration, or any effective range or value therein, as done anddetermined using known methods, as described herein or known in therelevant arts.

CITATIONS

All publications or patents cited herein, whether or not specificallydesignated, are entirely incorporated herein by reference as they showthe state of the art at the time of the present invention and/or toprovide description and enablement of the present invention.Publications refer to any scientific or patent publications, or anyother information available in any media format, including all recorded,electronic or printed formats. The following references are entirelyincorporated herein by reference: Ausubel, et al., ed., CurrentProtocols in Molecular Biology, John Wiley & Sons, Inc., NY, NY(1987-2001); Sambrook, et al., Molecular Cloning: A Laboratory Manual,2^(nd) Edition, Cold Spring Harbor, N.Y. (1989); Harlow and Lane,antibodies, a Laboratory Manual, Cold Spring Harbor, N.Y. (1989);Colligan, et al., eds., Current Protocols in Immunology, John Wiley &Sons, Inc., NY (1994-2001); Colligan et al., Current Protocols inProtein Science, John Wiley & Sons, NY, NY, (1997-2001).

Antibodies of the Present Invention—Production and Generation

At least one anti-IL-23 antibody used in the method of the presentinvention can be optionally produced by a cell line, a mixed cell line,an immortalized cell or clonal population of immortalized cells, as wellknown in the art. See, e.g., Ausubel, et al., ed., Current Protocols inMolecular Biology, John Wiley & Sons, Inc., NY, NY (1987-2001);Sambrook, et al., Molecular Cloning: A Laboratory Manual, 2^(nd)Edition, Cold Spring Harbor, N.Y. (1989); Harlow and Lane, antibodies, aLaboratory Manual, Cold Spring Harbor, N.Y. (1989); Colligan, et al.,eds., Current Protocols in Immunology, John Wiley & Sons, Inc., NY(1994-2001); Colligan et al., Current Protocols in Protein Science, JohnWiley & Sons, NY, NY, (1997-2001), each entirely incorporated herein byreference.

A preferred anti-IL-23 antibody is guselkumab (also referred to asCNTO1959) having the heavy chain variable region amino acid sequence ofSEQ ID NO: 106 and the light chain variable region amino acid sequenceof SEQ ID NO: 116 and having the heavy chain CDR amino acid sequences ofSEQ ID NO: 5, SEQ ID NO: 20, and SEQ ID NO: 44; and the light chain CDRamino acid sequences of SEQ ID NO: 50, SEQ ID NO: 56, and SEQ ID NO: 73.Other anti-IL-23 antibodies have sequences listed herein and aredescribed in U.S. Pat. No. 7,935,344, the entire contents of which areincorporated herein by reference).

Human antibodies that are specific for human IL-23 proteins or fragmentsthereof can be raised against an appropriate immunogenic antigen, suchas an isolated IL-23 protein and/or a portion thereof (includingsynthetic molecules, such as synthetic peptides). Other specific orgeneral mammalian antibodies can be similarly raised. Preparation ofimmunogenic antigens, and monoclonal antibody production can beperformed using any suitable technique.

In one approach, a hybridoma is produced by fusing a suitable immortalcell line (e.g., a myeloma cell line, such as, but not limited to,Sp2/0, Sp2/0-AG14, NSO, NS1, NS2, AE-1, L.5, L243, P3X63Ag8.653, Sp2SA3, Sp2 MAI, Sp2 SS1, Sp2 SA5, U937, MLA 144, ACT IV, MOLT4, DA-1,JURKAT, WEHI, K-562, COS, RAJI, NIH 3T3, HL-60, MLA 144, NAMALWA, NEURO2A, or the like, or heteromylomas, fusion products thereof, or any cellor fusion cell derived therefrom, or any other suitable cell line asknown in the art) (see, e.g., www.atcc.org, www.lifetech.com., and thelike), with antibody producing cells, such as, but not limited to,isolated or cloned spleen, peripheral blood, lymph, tonsil, or otherimmune or B cell containing cells, or any other cells expressing heavyor light chain constant or variable or framework or CDR sequences,either as endogenous or heterologous nucleic acid, as recombinant orendogenous, viral, bacterial, algal, prokaryotic, amphibian, insect,reptilian, fish, mammalian, rodent, equine, ovine, goat, sheep, primate,eukaryotic, genomic DNA, cDNA, rDNA, mitochondrial DNA or RNA,chloroplast DNA or RNA, hnRNA, mRNA, tRNA, single, double or triplestranded, hybridized, and the like or any combination thereof. See,e.g., Ausubel, supra, and Colligan, Immunology, supra, chapter 2,entirely incorporated herein by reference.

Antibody producing cells can also be obtained from the peripheral bloodor, preferably, the spleen or lymph nodes, of humans or other suitableanimals that have been immunized with the antigen of interest. Any othersuitable host cell can also be used for expressing heterologous orendogenous nucleic acid encoding an antibody, specified fragment orvariant thereof, of the present invention. The fused cells (hybridomas)or recombinant cells can be isolated using selective culture conditionsor other suitable known methods, and cloned by limiting dilution or cellsorting, or other known methods. Cells which produce antibodies with thedesired specificity can be selected by a suitable assay (e.g., ELISA).

Other suitable methods of producing or isolating antibodies of therequisite specificity can be used, including, but not limited to,methods that select recombinant antibody from a peptide or proteinlibrary (e.g., but not limited to, a bacteriophage, ribosome,oligonucleotide, RNA, cDNA, or the like, display library; e.g., asavailable from Cambridge antibody Technologies, Cambridgeshire, UK;MorphoSys, Martinsreid/Planegg, DE; Biovation, Aberdeen, Scotland, UK;Biolnvent, Lund, Sweden; Dyax Corp., Enzon, Affymax/Biosite; Xoma,Berkeley, Calif.; Ixsys. See, e.g., EP 368,684, PCT/GB91/01134;PCT/GB92/01755; PCT/GB92/002240; PCT/GB92/00883; PCT/GB93/00605; U.S.Ser. No. 08/350,260(5/12/94); PCT/GB94/01422; PCT/GB94/02662;PCT/GB97/01835; (CAT/MRC); WO90/14443; WO90/14424; WO90/14430;PCT/US94/1234; WO92/18619; WO96/07754; (Scripps); WO96/13583, WO97/08320(MorphoSys); WO95/16027 (Biolnvent); WO88/06630; WO90/3809 (Dyax); U.S.Pat. No. 4,704,692 (Enzon); PCT/US91/02989 (Affymax); WO89/06283; EP 371998; EP 550 400; (Xoma); EP 229 046; PCT/US91/07149 (Ixsys); orstochastically generated peptides or proteins—U.S. Pat. Nos. 5,723,323,5,763,192, 5,814,476, 5,817,483, 5,824,514, 5,976,862, WO 86/05803, EP590 689 (Ixsys, predecessor of Applied Molecular Evolution (AME), eachentirely incorporated herein by reference)) or that rely uponimmunization of transgenic animals (e.g., SCID mice, Nguyen et al.,Microbiol. Immunol. 41:901-907 (1997); Sandhu et al., Crit. Rev.Biotechnol. 16:95-118 (1996); Eren et al., Immunol. 93:154-161 (1998),each entirely incorporated by reference as well as related patents andapplications) that are capable of producing a repertoire of humanantibodies, as known in the art and/or as described herein. Suchtechniques, include, but are not limited to, ribosome display (Hanes etal., Proc. Natl. Acad. Sci. USA, 94:4937-4942 (May 1997); Hanes et al.,Proc. Natl. Acad. Sci. USA, 95:14130-14135 (November 1998)); single cellantibody producing technologies (e.g., selected lymphocyte antibodymethod (“SLAM”) (U.S. Pat. No. 5,627,052, Wen et al., J. Immunol.17:887-892 (1987); Babcook et al., Proc. Natl. Acad. Sci. USA93:7843-7848 (1996)); gel microdroplet and flow cytometry (Powell etal., Biotechnol. 8:333-337 (1990); One Cell Systems, Cambridge, Mass.;Gray et al., J. Imm. Meth. 182:155-163 (1995); Kenny et al.,Bio/Technol. 13:787-790 (1995)); B-cell selection (Steenbakkers et al.,Molec. Biol. Reports 19:125-134 (1994); Jonak et al., Progress Biotech,Vol. 5, In Vitro Immunization in Hybridoma Technology, Borrebaeck, ed.,Elsevier Science Publishers B.V., Amsterdam, Netherlands (1988)).

Methods for engineering or humanizing non-human or human antibodies canalso be used and are well known in the art. Generally, a humanized orengineered antibody has one or more amino acid residues from a sourcethat is non-human, e.g., but not limited to, mouse, rat, rabbit,non-human primate or other mammal. These non-human amino acid residuesare replaced by residues often referred to as “import” residues, whichare typically taken from an “import” variable, constant or other domainof a known human sequence.

Known human Ig sequences are disclosed, e.g.,www.ncbi.nlm.nih.gov/entrez/query.fcgi; www.ncbi.nih.gov/igblast;www.atcc.org/phage/hdb.html; www.mrc-cpe.cam.ac.uk/ALIGNMENTS.php;www.kabatdatabase.com/top.html; ftp.ncbi.nih.gov/repository/kabat;www.sciquest.com; www.abcam.com;www.antibodyresource.com/onlinecomp.html;www.public.iastate.edu/˜pedro/research tools.html;www.whfreeman.com/immunology/CH05/kuby05.htm;www.hhmi.org/grants/lectures/1996/vlab;www.path.cam.ac.uk/˜mrc7/mikeimages.html;mcb.harvard.edu/BioLinks/Immunology.html; www.immunologylink.com;pathbox.wustl.edu/˜hcenter/index.html; www.appliedbiosystems.com;www.nal.usda.gov/awic/pubs/antibody;www.m.ehime-u.ac.jp/˜yasuhito/Elisa.html; www.biodesign.com;www.cancerresearchuk.org; www.biotech.ufl.edu; www.isac-net.org;baserv.uci.kun.nl/˜jraats/linksl.html;www.recab.uni-hd.de/immuno.bme.nwu.edu; www.mrc-cpe.cam.ac.uk;www.ibt.unam.mx/vir/V_mice.html; http://www.bioinforg.uk/abs;antibody.bath.ac.uk; www.unizh.ch; www.cryst.bbk.ac.uk/˜ubcg07s;www.nimr.mrc.ac.uk/CC/ccaewg/ccaewg.html;www.path.cam.ac.uk/˜mrc7/humanisation/TAHHP.html;www.ibt.unam.mx/vir/structure/stat_aim.html;www.biosci.missouri.edu/smithgp/index.html; www.jerini.de; Kabat et al.,Sequences of Proteins of Immunological Interest, U.S. Dept. Health(1983), each entirely incorporated herein by reference.

Such imported sequences can be used to reduce immunogenicity or reduce,enhance or modify binding, affinity, on-rate, off-rate, avidity,specificity, half-life, or any other suitable characteristic, as knownin the art. In general, the CDR residues are directly and mostsubstantially involved in influencing antigen binding. Accordingly, partor all of the non-human or human CDR sequences are maintained while thenon-human sequences of the variable and constant regions may be replacedwith human or other amino acids.

Antibodies can also optionally be humanized or human antibodiesengineered with retention of high affinity for the antigen and otherfavorable biological properties. To achieve this goal, humanized (orhuman) antibodies can be optionally prepared by a process of analysis ofthe parental sequences and various conceptual humanized products usingthree-dimensional models of the parental and humanized sequences.Three-dimensional immunoglobulin models are commonly available and arefamiliar to those skilled in the art. Computer programs are availablewhich illustrate and display probable three-dimensional conformationalstructures of selected candidate immunoglobulin sequences. Inspection ofthese displays permits analysis of the likely role of the residues inthe functioning of the candidate immunoglobulin sequence, i.e., theanalysis of residues that influence the ability of the candidateimmunoglobulin to bind its antigen. In this way, framework (FR) residuescan be selected and combined from the consensus and import sequences sothat the desired antibody characteristic, such as increased affinity forthe target antigen(s), is achieved.

In addition, the human IL-23 specific antibody used in the method of thepresent invention may comprise a human germline light chain framework.In particular embodiments, the light chain germline sequence is selectedfrom human VK sequences including, but not limited to, A1, A10, A11,A14, A17, A18, A19, A2, A20, A23, A26, A27, A3, A30, A5, A7, B2, B3, L1,L10, L11, L12, L14, L15, L16, L18, L19, L2, L20, L22, L23, L24, L25,L4/18a, L5, L6, L8, L9, O1, O11, O12, O14, O18, O2, O4, and O8. Incertain embodiments, this light chain human germline framework isselected from V1-11, V1-13, V1-16, V1-17, V1-18, V1-19, V1-2, V1-20,V1-22, V1-3, V1-4, V1-5, V1-7, V1-9, V2-1, V2-11, V2-13, V2-14, V2-15,V2-17, V2-19, V2-6, V2-7, V2-8, V3-2, V3-3, V3-4, V4-1, V4-2, V4-3,V4-4, V4-6, V5-1, V5-2, V5-4, and V5-6.

In other embodiments, the human IL-23 specific antibody used in themethod of the present invention may comprise a human germline heavychain framework. In particular embodiments, this heavy chain humangermline framework is selected from VH1-18, VH1-2, VH1-24, VH1-3,VH1-45, VH1-46, VH1-58, VH1-69, VH1-8, VH2-26, VH2-5, VH2-70, VH3-11,VH3-13, VH3-15, VH3-16, VH3-20, VH3-21, VH3-23, VH3-30, VH3-33, VH3-35,VH3-38, VH3-43, VH3-48, VH3-49, VH3-53, VH3-64, VH3-66, VH3-7, VH3-72,VH3-73, VH3-74, VH3-9, VH4-28, VH4-31, VH4-34, VH4-39, VH4-4, VH4-59,VH4-61, VH5-51, VH6-1, and VH7-81.

In particular embodiments, the light chain variable region and/or heavychain variable region comprises a framework region or at least a portionof a framework region (e.g., containing 2 or 3 subregions, such as FR2and FR3). In certain embodiments, at least FRL1, FRL2, FRL3, or FRL4 isfully human. In other embodiments, at least FRH1, FRH2, FRH3, or FRH4 isfully human. In some embodiments, at least FRL1, FRL2, FRL3, or FRL4 isa germline sequence (e.g., human germline) or comprises human consensussequences for the particular framework (readily available at the sourcesof known human Ig sequences described above). In other embodiments, atleast FRH1, FRH2, FRH3, or FRH4 is a germline sequence (e.g., humangermline) or comprises human consensus sequences for the particularframework. In preferred embodiments, the framework region is a fullyhuman framework region.

Humanization or engineering of antibodies of the present invention canbe performed using any known method, such as but not limited to thosedescribed in, Winter (Jones et al., Nature 321:522 (1986); Riechmann etal., Nature 332:323 (1988); Verhoeyen et al., Science 239:1534 (1988)),Sims et al., J. Immunol. 151: 2296 (1993); Chothia and Lesk, J. Mol.Biol. 196:901 (1987), Carter et al., Proc. Natl. Acad. Sci. U.S.A.89:4285 (1992); Presta et al., J. Immunol. 151:2623 (1993), U.S. Pat.Nos. 5,723,323, 5,976,862, 5,824,514, 5,817,483, 5,814,476, 5,763,192,5,723,323, 5,766886, 5714352, 6204023, 6180370, 5693762, 5530101,5585089, 5225539; 4816567, PCT/: US98/16280, US96/18978, US91/09630,US91/05939, US94/01234, GB89/01334, GB91/01134, GB92/01755; WO90/14443,WO90/14424, WO90/14430, EP 229246, each entirely incorporated herein byreference, included references cited therein.

In certain embodiments, the antibody comprises an altered (e.g.,mutated) Fc region. For example, in some embodiments, the Fc region hasbeen altered to reduce or enhance the effector functions of theantibody. In some embodiments, the Fc region is an isotype selected fromIgM, IgA, IgG, IgE, or other isotype. Alternatively, or additionally, itmay be useful to combine amino acid modifications with one or morefurther amino acid modifications that alter C1q binding and/or thecomplement dependent cytotoxicity function of the Fc region of an IL-23binding molecule. The starting polypeptide of particular interest may beone that binds to C1q and displays complement dependent cytotoxicity(CDC). Polypeptides with pre-existing C1q binding activity, optionallyfurther having the ability to mediate CDC may be modified such that oneor both of these activities are enhanced. Amino acid modifications thatalter C1q and/or modify its complement dependent cytotoxicity functionare described, for example, in WO0042072, which is hereby incorporatedby reference.

As disclosed above, one can design an Fc region of the human IL-23specific antibody of the present invention with altered effectorfunction, e.g., by modifying C1q binding and/or FcγR binding and therebychanging complement dependent cytotoxicity (CDC) activity and/orantibody-dependent cell-mediated cytotoxicity (ADCC) activity. “Effectorfunctions” are responsible for activating or diminishing a biologicalactivity (e.g., in a subject). Examples of effector functions include,but are not limited to: C1q binding; CDC; Fc receptor binding; ADCC;phagocytosis; down regulation of cell surface receptors (e.g., B cellreceptor; BCR), etc. Such effector functions may require the Fc regionto be combined with a binding domain (e.g., an antibody variable domain)and can be assessed using various assays (e.g., Fc binding assays, ADCCassays, CDC assays, etc.).

For example, one can generate a variant Fc region of the human IL-23 (oranti-IL-23) antibody with improved C1q binding and improvedFcγRIIIbinding (e.g., having both improved ADCC activity and improvedCDC activity). Alternatively, if it is desired that effector function bereduced or ablated, a variant Fc region can be engineered with reducedCDC activity and/or reduced ADCC activity. In other embodiments, onlyone of these activities may be increased, and, optionally, also theother activity reduced (e.g., to generate an Fc region variant withimproved ADCC activity, but reduced CDC activity and vice versa).

Fc mutations can also be introduced in engineer to alter theirinteraction with the neonatal Fc receptor (FcRn) and improve theirpharmacokinetic properties. A collection of human Fc variants withimproved binding to the FcRn have been described (Shields et al.,(2001). High resolution mapping of the binding site on human IgG1 forFcγRI, FcγRII, FcγRIII, and FcRn and design of IgG1 variants withimproved binding to the FcγR, J. Biol. Chem. 276:6591-6604).

Another type of amino acid substitution serves to alter theglycosylation pattern of the Fc region of the human IL-23 specificantibody. Glycosylation of an Fc region is typically either N-linked orO-linked. N-linked refers to the attachment of the carbohydrate moietyto the side chain of an asparagine residue. O-linked glycosylationrefers to the attachment of one of the sugars N-aceylgalactosamine,galactose, or xylose to a hydroxyamino acid, most commonly serine orthreonine, although 5-hydroxyproline or 5-hydroxylysine may also beused. The recognition sequences for enzymatic attachment of thecarbohydrate moiety to the asparagine side chain peptide sequences areasparagine-X-serine and asparagine-X-threonine, where X is any aminoacid except proline. Thus, the presence of either of these peptidesequences in a polypeptide creates a potential glycosylation site.

The glycosylation pattern may be altered, for example, by deleting oneor more glycosylation site(s) found in the polypeptide, and/or addingone or more glycosylation sites that are not present in the polypeptide.Addition of glycosylation sites to the Fc region of a human IL-23specific antibody is conveniently accomplished by altering the aminoacid sequence such that it contains one or more of the above-describedtripeptide sequences (for N-linked glycosylation sites). An exemplaryglycosylation variant has an amino acid substitution of residue Asn 297of the heavy chain. The alteration may also be made by the addition of,or substitution by, one or more serine or threonine residues to thesequence of the original polypeptide (for O-linked glycosylation sites).Additionally, a change of Asn 297 to Ala can remove one of theglycosylation sites.

In certain embodiments, the human IL-23 specific antibody of the presentinvention is expressed in cells that express beta(1,4)-N-acetylglucosaminyltransferase III (GnT III), such that GnT IIIadds GlcNAc to the human IL-23 antibody. Methods for producingantibodies in such a fashion are provided in WO/9954342, WO/03011878,patent publication 20030003097A1, and Umana et al., NatureBiotechnology, 17:176-180, Feb. 1999; all of which are hereinspecifically incorporated by reference in their entireties.

The anti-IL-23 antibody can also be optionally generated by immunizationof a transgenic animal (e.g., mouse, rat, hamster, non-human primate,and the like) capable of producing a repertoire of human antibodies, asdescribed herein and/or as known in the art. Cells that produce a humananti-IL-23 antibody can be isolated from such animals and immortalizedusing suitable methods, such as the methods described herein.

Transgenic mice that can produce a repertoire of human antibodies thatbind to human antigens can be produced by known methods (e.g., but notlimited to, U.S. Pat. Nos. 5,770,428, 5,569,825, 5,545,806, 5,625,126,5,625,825, 5,633,425, 5,661,016 and 5,789,650 issued to Lonberg et al.;Jakobovits et al. WO 98/50433, Jakobovits et al. WO 98/24893, Lonberg etal. WO 98/24884, Lonberg et al. WO 97/13852, Lonberg et al. WO 94/25585,Kucherlapate et al. WO 96/34096, Kucherlapate et al. EP 0463 151 B1,Kucherlapate et al. EP 0710 719 A1, Surani et al. U.S. Pat. No.5,545,807, Bruggemann et al. WO 90/04036, Bruggemann et al. EP 0438 474B1, Lonberg et al. EP 0814 259 A2, Lonberg et al. GB 2 272 440 A,Lonberg et al. Nature 368:856-859 (1994), Taylor et al., Int. Immunol.6(4)579-591 (1994), Green et al, Nature Genetics 7:13-21 (1994), Mendezet al., Nature Genetics 15:146-156 (1997), Taylor et al., Nucleic AcidsResearch 20(23):6287-6295 (1992), Tuaillon et al., Proc Natl Acad SciUSA 90(8)3720-3724 (1993), Lonberg et al., Int Rev Immunol 13(1):65-93(1995) and Fishwald et al., Nat Biotechnol 14(7):845-851 (1996), whichare each entirely incorporated herein by reference). Generally, thesemice comprise at least one transgene comprising DNA from at least onehuman immunoglobulin locus that is functionally rearranged, or which canundergo functional rearrangement. The endogenous immunoglobulin loci insuch mice can be disrupted or deleted to eliminate the capacity of theanimal to produce antibodies encoded by endogenous genes.

Screening antibodies for specific binding to similar proteins orfragments can be conveniently achieved using peptide display libraries.This method involves the screening of large collections of peptides forindividual members having the desired function or structure. Antibodyscreening of peptide display libraries is well known in the art. Thedisplayed peptide sequences can be from 3 to 5000 or more amino acids inlength, frequently from 5-100 amino acids long, and often from about 8to 25 amino acids long. In addition to direct chemical synthetic methodsfor generating peptide libraries, several recombinant DNA methods havebeen described. One type involves the display of a peptide sequence onthe surface of a bacteriophage or cell. Each bacteriophage or cellcontains the nucleotide sequence encoding the particular displayedpeptide sequence. Such methods are described in PCT Patent PublicationNos. 91/17271, 91/18980, 91/19818, and 93/08278.

Other systems for generating libraries of peptides have aspects of bothin vitro chemical synthesis and recombinant methods. See, PCT PatentPublication Nos. 92/05258, 92/14843, and 96/19256. See also, U.S. Pat.Nos. 5,658,754; and 5,643,768. Peptide display libraries, vector, andscreening kits are commercially available from such suppliers asInvitrogen (Carlsbad, Calif.), and Cambridge antibody Technologies(Cambridgeshire, UK). See, e.g., U.S. Pat. Nos. 4,704,692, 4,939,666,4,946,778, 5,260,203, 5,455,030, 5,518,889, 5,534,621, 5,656,730,5,763,733, 5,767,260, 5,856,456, assigned to Enzon; U.S. Pat. Nos.5,223,409, 5,403,484, 5,571,698, 5,837,500, assigned to Dyax, 5427908,5580717, assigned to Affymax; 5885793, assigned to Cambridge antibodyTechnologies; 5750373, assigned to Genentech, 5618920, 5595898, 5576195,5698435, 5693493, 5698417, assigned to Xoma, Colligan, supra; Ausubel,supra; or Sambrook, supra, each of the above patents and publicationsentirely incorporated herein by reference.

Antibodies used in the method of the present invention can also beprepared using at least one anti-IL23 antibody encoding nucleic acid toprovide transgenic animals or mammals, such as goats, cows, horses,sheep, rabbits, and the like, that produce such antibodies in theirmilk. Such animals can be provided using known methods. See, e.g., butnot limited to, U.S. Pat. Nos. 5,827,690; 5,849,992; 4,873,316;5,849,992; 5,994,616; 5,565,362; 5,304,489, and the like, each of whichis entirely incorporated herein by reference.

Antibodies used in the method of the present invention can additionallybe prepared using at least one anti-IL23 antibody encoding nucleic acidto provide transgenic plants and cultured plant cells (e.g., but notlimited to, tobacco and maize) that produce such antibodies, specifiedportions or variants in the plant parts or in cells cultured therefrom.As a non-limiting example, transgenic tobacco leaves expressingrecombinant proteins have been successfully used to provide largeamounts of recombinant proteins, e.g., using an inducible promoter. See,e.g., Cramer et al., Curr. Top. Microbol. Immunol. 240:95-118 (1999) andreferences cited therein. Also, transgenic maize have been used toexpress mammalian proteins at commercial production levels, withbiological activities equivalent to those produced in other recombinantsystems or purified from natural sources. See, e.g., Hood et al., Adv.Exp. Med. Biol. 464:127-147 (1999) and references cited therein.Antibodies have also been produced in large amounts from transgenicplant seeds including antibody fragments, such as single chainantibodies (scFv's), including tobacco seeds and potato tubers. See,e.g., Conrad et al., Plant Mol. Biol. 38:101-109 (1998) and referencescited therein. Thus, antibodies of the present invention can also beproduced using transgenic plants, according to known methods. See also,e.g., Fischer et al., Biotechnol. Appl. Biochem. 30:99-108 (October,1999), Ma et al., Trends Biotechnol. 13:522-7 (1995); Ma et al., PlantPhysiol. 109:341-6 (1995); Whitelam et al., Biochem. Soc. Trans.22:940-944 (1994); and references cited therein. Each of the abovereferences is entirely incorporated herein by reference.

The antibodies used in the method of the invention can bind human IL-23with a wide range of affinities (K_(D)). In a preferred embodiment, ahuman mAb can optionally bind human IL-23 with high affinity. Forexample, a human mAb can bind human IL-23 with a K_(D) equal to or lessthan about 10⁻⁷M, such as but not limited to, 0.1-9.9 (or any range orvalue therein)×10⁻⁷, 10⁻⁸, 10⁻⁹, 10⁻¹⁰, 10⁻¹¹, 10⁻¹², 10⁻¹³ or any rangeor value therein.

The affinity or avidity of an antibody for an antigen can be determinedexperimentally using any suitable method. (See, for example, Berzofsky,et al., “Antibody-Antigen Interactions,” In Fundamental Immunology,Paul, W. E., Ed., Raven Press: New York, N.Y. (1984); Kuby, JanisImmunology, W. H. Freeman and Company: New York, N.Y. (1992); andmethods described herein). The measured affinity of a particularantibody-antigen interaction can vary if measured under differentconditions (e.g., salt concentration, pH). Thus, measurements ofaffinity and other antigen-binding parameters (e.g., K_(D), K_(a),K_(d)) are preferably made with standardized solutions of antibody andantigen, and a standardized buffer, such as the buffer described herein.

Nucleic Acid Molecules

Using the information provided herein, for example, the nucleotidesequences encoding at least 70-100% of the contiguous amino acids of atleast one of the light or heavy chain variable or CDR regions describedherein, among other sequences disclosed herein, specified fragments,variants or consensus sequences thereof, or a deposited vectorcomprising at least one of these sequences, a nucleic acid molecule ofthe present invention encoding at least one anti-IL-23 antibody can beobtained using methods described herein or as known in the art.

Nucleic acid molecules of the present invention can be in the form ofRNA, such as mRNA, hnRNA, tRNA or any other form, or in the form of DNA,including, but not limited to, cDNA and genomic DNA obtained by cloningor produced synthetically, or any combinations thereof. The DNA can betriple-stranded, double-stranded or single-stranded, or any combinationthereof. Any portion of at least one strand of the DNA or RNA can be thecoding strand, also known as the sense strand, or it can be thenon-coding strand, also referred to as the anti-sense strand.

Isolated nucleic acid molecules used in the method of the presentinvention can include nucleic acid molecules comprising an open readingframe (ORF), optionally, with one or more introns, e.g., but not limitedto, at least one specified portion of at least one CDR, such as CDR1,CDR2 and/or CDR3 of at least one heavy chain or light chain; nucleicacid molecules comprising the coding sequence for an anti-IL-23 antibodyor variable region; and nucleic acid molecules which comprise anucleotide sequence substantially different from those described abovebut which, due to the degeneracy of the genetic code, still encode atleast one anti-IL-23 antibody as described herein and/or as known in theart. Of course, the genetic code is well known in the art. Thus, itwould be routine for one skilled in the art to generate such degeneratenucleic acid variants that code for specific anti-IL-23 antibodies usedin the method of the present invention. See, e.g., Ausubel, et al.,supra, and such nucleic acid variants are included in the presentinvention. Non-limiting examples of isolated nucleic acid moleculesinclude nucleic acids encoding HC CDR1, HC CDR2, HC CDR3, LC CDR1, LCCDR2, and LC CDR3, respectively.

As indicated herein, nucleic acid molecules which comprise a nucleicacid encoding an anti-IL-23 antibody can include, but are not limitedto, those encoding the amino acid sequence of an antibody fragment, byitself; the coding sequence for the entire antibody or a portionthereof; the coding sequence for an antibody, fragment or portion, aswell as additional sequences, such as the coding sequence of at leastone signal leader or fusion peptide, with or without the aforementionedadditional coding sequences, such as at least one intron, together withadditional, non-coding sequences, including but not limited to,non-coding 5′ and 3′ sequences, such as the transcribed, non-translatedsequences that play a role in transcription, mRNA processing, includingsplicing and polyadenylation signals (for example, ribosome binding andstability of mRNA); an additional coding sequence that codes foradditional amino acids, such as those that provide additionalfunctionalities. Thus, the sequence encoding an antibody can be fused toa marker sequence, such as a sequence encoding a peptide thatfacilitates purification of the fused antibody comprising an antibodyfragment or portion.

Polynucleotides Selectively Hybridizing to a Polynucleotide as DescribedHerein

The method of the present invention uses isolated nucleic acids thathybridize under selective hybridization conditions to a polynucleotidedisclosed herein. Thus, the polynucleotides of this embodiment can beused for isolating, detecting, and/or quantifying nucleic acidscomprising such polynucleotides. For example, polynucleotides of thepresent invention can be used to identify, isolate, or amplify partialor full-length clones in a deposited library. In some embodiments, thepolynucleotides are genomic or cDNA sequences isolated, or otherwisecomplementary to, a cDNA from a human or mammalian nucleic acid library.

Preferably, the cDNA library comprises at least 80% full-lengthsequences, preferably, at least 85% or 90% full-length sequences, and,more preferably, at least 95% full-length sequences. The cDNA librariescan be normalized to increase the representation of rare sequences. Lowor moderate stringency hybridization conditions are typically, but notexclusively, employed with sequences having a reduced sequence identityrelative to complementary sequences. Moderate and high stringencyconditions can optionally be employed for sequences of greater identity.Low stringency conditions allow selective hybridization of sequenceshaving about 70% sequence identity and can be employed to identifyorthologous or paralogous sequences.

Optionally, polynucleotides will encode at least a portion of anantibody. The polynucleotides embrace nucleic acid sequences that can beemployed for selective hybridization to a polynucleotide encoding anantibody of the present invention. See, e.g., Ausubel, supra; Colligan,supra, each entirely incorporated herein by reference.

Construction of Nucleic Acids

The isolated nucleic acids can be made using (a) recombinant methods,(b) synthetic techniques, (c) purification techniques, and/or (d)combinations thereof, as well-known in the art.

The nucleic acids can conveniently comprise sequences in addition to apolynucleotide of the present invention. For example, a multi-cloningsite comprising one or more endonuclease restriction sites can beinserted into the nucleic acid to aid in isolation of thepolynucleotide. Also, translatable sequences can be inserted to aid inthe isolation of the translated polynucleotide of the present invention.For example, a hexa-histidine marker sequence provides a convenientmeans to purify the proteins of the present invention. The nucleic acidof the present invention, excluding the coding sequence, is optionally avector, adapter, or linker for cloning and/or expression of apolynucleotide of the present invention.

Additional sequences can be added to such cloning and/or expressionsequences to optimize their function in cloning and/or expression, toaid in isolation of the polynucleotide, or to improve the introductionof the polynucleotide into a cell. Use of cloning vectors, expressionvectors, adapters, and linkers is well known in the art. (See, e.g.,Ausubel, supra; or Sambrook, supra)

Recombinant Methods for Constructing Nucleic Acids

The isolated nucleic acid compositions, such as RNA, cDNA, genomic DNA,or any combination thereof, can be obtained from biological sourcesusing any number of cloning methodologies known to those of skill in theart. In some embodiments, oligonucleotide probes that selectivelyhybridize, under stringent conditions, to the polynucleotides of thepresent invention are used to identify the desired sequence in a cDNA orgenomic DNA library. The isolation of RNA, and construction of cDNA andgenomic libraries, are well known to those of ordinary skill in the art.(See, e.g., Ausubel, supra; or Sambrook, supra)

Nucleic Acid Screening and Isolation Methods

A cDNA or genomic library can be screened using a probe based upon thesequence of a polynucleotide used in the method of the presentinvention, such as those disclosed herein. Probes can be used tohybridize with genomic DNA or cDNA sequences to isolate homologous genesin the same or different organisms. Those of skill in the art willappreciate that various degrees of stringency of hybridization can beemployed in the assay; and either the hybridization or the wash mediumcan be stringent. As the conditions for hybridization become morestringent, there must be a greater degree of complementarity between theprobe and the target for duplex formation to occur. The degree ofstringency can be controlled by one or more of temperature, ionicstrength, pH and the presence of a partially denaturing solvent, such asformamide. For example, the stringency of hybridization is convenientlyvaried by changing the polarity of the reactant solution through, forexample, manipulation of the concentration of formamide within the rangeof 0% to 50%. The degree of complementarity (sequence identity) requiredfor detectable binding will vary in accordance with the stringency ofthe hybridization medium and/or wash medium. The degree ofcomplementarity will optimally be 100%, or 70-100%, or any range orvalue therein. However, it should be understood that minor sequencevariations in the probes and primers can be compensated for by reducingthe stringency of the hybridization and/or wash medium.

Methods of amplification of RNA or DNA are well known in the art and canbe used according to the present invention without undueexperimentation, based on the teaching and guidance presented herein.

Known methods of DNA or RNA amplification include, but are not limitedto, polymerase chain reaction (PCR) and related amplification processes(see, e.g., U.S. Pat. Nos. 4,683,195, 4,683,202, 4,800,159, 4,965,188,to Mullis, et al.; U.S. Pat. Nos. 4,795,699 and 4,921,794 to Tabor, etal; U.S. Pat. No. 5,142,033 to Innis; U.S. Pat. No. 5,122,464 to Wilson,et al.; U.S. Pat. No. 5,091,310 to Innis; U.S. Pat. No. 5,066,584 toGyllensten, et al; U.S. Pat. No. 4,889,818 to Gelfand, et al; U.S. Pat.No. 4,994,370 to Silver, et al; U.S. Pat. No. 4,766,067 to Biswas; U.S.Pat. No. 4,656,134 to Ringold) and RNA mediated amplification that usesanti-sense RNA to the target sequence as a template for double-strandedDNA synthesis (U.S. Pat. No. 5,130,238 to Malek, et al, with thetradename NASBA), the entire contents of which references areincorporated herein by reference. (See, e.g., Ausubel, supra; orSambrook, supra.)

For instance, polymerase chain reaction (PCR) technology can be used toamplify the sequences of polynucleotides used in the method of thepresent invention and related genes directly from genomic DNA or cDNAlibraries. PCR and other in vitro amplification methods can also beuseful, for example, to clone nucleic acid sequences that code forproteins to be expressed, to make nucleic acids to use as probes fordetecting the presence of the desired mRNA in samples, for nucleic acidsequencing, or for other purposes. Examples of techniques sufficient todirect persons of skill through in vitro amplification methods are foundin Berger, supra, Sambrook, supra, and Ausubel, supra, as well asMullis, et al., U.S. Pat. No. 4,683,202 (1987); and Innis, et al., PCRProtocols A Guide to Methods and Applications, Eds., Academic PressInc., San Diego, Calif. (1990). Commercially available kits for genomicPCR amplification are known in the art. See, e.g., Advantage-GC GenomicPCR Kit (Clontech). Additionally, e.g., the T4 gene 32 protein(Boehringer Mannheim) can be used to improve yield of long PCR products.

Synthetic Methods for Constructing Nucleic Acids

The isolated nucleic acids used in the method of the present inventioncan also be prepared by direct chemical synthesis by known methods (see,e.g., Ausubel, et al., supra). Chemical synthesis generally produces asingle-stranded oligonucleotide, which can be converted intodouble-stranded DNA by hybridization with a complementary sequence, orby polymerization with a DNA polymerase using the single strand as atemplate. One of skill in the art will recognize that while chemicalsynthesis of DNA can be limited to sequences of about 100 or more bases,longer sequences can be obtained by the ligation of shorter sequences.

Recombinant Expression Cassettes

The present invention uses recombinant expression cassettes comprising anucleic acid. A nucleic acid sequence, for example, a cDNA or a genomicsequence encoding an antibody used in the method of the presentinvention, can be used to construct a recombinant expression cassettethat can be introduced into at least one desired host cell. Arecombinant expression cassette will typically comprise a polynucleotideoperably linked to transcriptional initiation regulatory sequences thatwill direct the transcription of the polynucleotide in the intended hostcell. Both heterologous and non-heterologous (i.e., endogenous)promoters can be employed to direct expression of the nucleic acids.

In some embodiments, isolated nucleic acids that serve as promoter,enhancer, or other elements can be introduced in the appropriateposition (upstream, downstream or in the intron) of a non-heterologousform of a polynucleotide of the present invention so as to up or downregulate expression of a polynucleotide. For example, endogenouspromoters can be altered in vivo or in vitro by mutation, deletionand/or substitution.

Vectors and Host Cells

The present invention also relates to vectors that include isolatednucleic acid molecules, host cells that are genetically engineered withthe recombinant vectors, and the production of at least one anti-IL-23antibody by recombinant techniques, as is well known in the art. See,e.g., Sambrook, et al., supra; Ausubel, et al., supra, each entirelyincorporated herein by reference.

The polynucleotides can optionally be joined to a vector containing aselectable marker for propagation in a host. Generally, a plasmid vectoris introduced in a precipitate, such as a calcium phosphate precipitate,or in a complex with a charged lipid. If the vector is a virus, it canbe packaged in vitro using an appropriate packaging cell line and thentransduced into host cells.

The DNA insert should be operatively linked to an appropriate promoter.The expression constructs will further contain sites for transcriptioninitiation, termination and, in the transcribed region, a ribosomebinding site for translation. The coding portion of the maturetranscripts expressed by the constructs will preferably include atranslation initiating at the beginning and a termination codon (e.g.,UAA, UGA or UAG) appropriately positioned at the end of the mRNA to betranslated, with UAA and UAG preferred for mammalian or eukaryotic cellexpression.

Expression vectors will preferably but optionally include at least oneselectable marker. Such markers include, e.g., but are not limited to,methotrexate (MTX), dihydrofolate reductase (DHFR, U.S. Pat. Nos.4,399,216; 4,634,665; 4,656,134; 4,956,288; 5,149,636; 5,179,017,ampicillin, neomycin (G418), mycophenolic acid, or glutamine synthetase(GS, U.S. Pat. Nos. 5,122,464; 5,770,359; 5,827,739) resistance foreukaryotic cell culture, and tetracycline or ampicillin resistance genesfor culturing in E. coli and other bacteria or prokaryotics (the abovepatents are entirely incorporated hereby by reference). Appropriateculture mediums and conditions for the above-described host cells areknown in the art. Suitable vectors will be readily apparent to theskilled artisan. Introduction of a vector construct into a host cell canbe effected by calcium phosphate transfection, DEAE-dextran mediatedtransfection, cationic lipid-mediated transfection, electroporation,transduction, infection or other known methods. Such methods aredescribed in the art, such as Sambrook, supra, Chapters 1-4 and 16-18;Ausubel, supra, Chapters 1, 9, 13, 15, 16.

At least one antibody used in the method of the present invention can beexpressed in a modified form, such as a fusion protein, and can includenot only secretion signals, but also additional heterologous functionalregions. For instance, a region of additional amino acids, particularlycharged amino acids, can be added to the N-terminus of an antibody toimprove stability and persistence in the host cell, during purification,or during subsequent handling and storage. Also, peptide moieties can beadded to an antibody of the present invention to facilitatepurification. Such regions can be removed prior to final preparation ofan antibody or at least one fragment thereof. Such methods are describedin many standard laboratory manuals, such as Sambrook, supra, Chapters17.29-17.42 and 18.1-18.74; Ausubel, supra, Chapters 16, 17 and 18.

Those of ordinary skill in the art are knowledgeable in the numerousexpression systems available for expression of a nucleic acid encoding aprotein used in the method of the present invention. Alternatively,nucleic acids can be expressed in a host cell by turning on (bymanipulation) in a host cell that contains endogenous DNA encoding anantibody. Such methods are well known in the art, e.g., as described inU.S. Pat. Nos. 5,580,734, 5,641,670, 5,733,746, and 5,733,761, entirelyincorporated herein by reference.

Illustrative of cell cultures useful for the production of theantibodies, specified portions or variants thereof, are mammalian cells.Mammalian cell systems often will be in the form of monolayers of cellsalthough mammalian cell suspensions or bioreactors can also be used. Anumber of suitable host cell lines capable of expressing intactglycosylated proteins have been developed in the art, and include theCOS-1 (e.g., ATCC CRL 1650), COS-7 (e.g., ATCC CRL-1651), HEK293, BHK21(e.g., ATCC CRL-10), CHO (e.g., ATCC CRL 1610) and BSC-1 (e.g., ATCCCRL-26) cell lines, Cos-7 cells, CHO cells, hep G2 cells, P3X63Ag8.653,SP2/0-Ag14, 293 cells, HeLa cells and the like, which are readilyavailable from, for example, American Type Culture Collection, Manassas,Va. (www.atcc.org). Preferred host cells include cells of lymphoidorigin, such as myeloma and lymphoma cells. Particularly preferred hostcells are P3X63Ag8.653 cells (ATCC Accession Number CRL-1580) andSP2/0-Ag14 cells (ATCC Accession Number CRL-1851). In a particularlypreferred embodiment, the recombinant cell is a P3X63Ab8.653 or aSP2/0-Ag14 cell.

Expression vectors for these cells can include one or more of thefollowing expression control sequences, such as, but not limited to, anorigin of replication; a promoter (e.g., late or early SV40 promoters,the CMV promoter (U.S. Pat. Nos. 5,168,062; 5,385,839), an HSV tkpromoter, a pgk (phosphoglycerate kinase) promoter, an EF-1 alphapromoter (U.S. Pat. No. 5,266,491), at least one human immunoglobulinpromoter; an enhancer, and/or processing information sites, such asribosome binding sites, RNA splice sites, polyadenylation sites (e.g.,an SV40 large T Ag poly A addition site), and transcriptional terminatorsequences. See, e.g., Ausubel et al., supra; Sambrook, et al., supra.Other cells useful for production of nucleic acids or proteins of thepresent invention are known and/or available, for instance, from theAmerican Type Culture Collection Catalogue of Cell Lines and Hybridomas(www.atcc.org) or other known or commercial sources.

When eukaryotic host cells are employed, polyadenlyation ortranscription terminator sequences are typically incorporated into thevector. An example of a terminator sequence is the polyadenlyationsequence from the bovine growth hormone gene. Sequences for accuratesplicing of the transcript can also be included. An example of asplicing sequence is the VP1 intron from SV40 (Sprague, et al., J.Virol. 45:773-781 (1983)). Additionally, gene sequences to controlreplication in the host cell can be incorporated into the vector, asknown in the art.

Purification of an Antibody

An anti-IL-23 antibody can be recovered and purified from recombinantcell cultures by well-known methods including, but not limited to,protein A purification, ammonium sulfate or ethanol precipitation, acidextraction, anion or cation exchange chromatography, phosphocellulosechromatography, hydrophobic interaction chromatography, affinitychromatography, hydroxylapatite chromatography and lectinchromatography. High performance liquid chromatography (“HPLC”) can alsobe employed for purification. See, e.g., Colligan, Current Protocols inImmunology, or Current Protocols in Protein Science, John Wiley & Sons,NY, NY, (1997-2001), e.g., Chapters 1, 4, 6, 8, 9, 10, each entirelyincorporated herein by reference.

Antibodies used in the method of the present invention include naturallypurified products, products of chemical synthetic procedures, andproducts produced by recombinant techniques from a eukaryotic host,including, for example, yeast, higher plant, insect and mammalian cells.Depending upon the host employed in a recombinant production procedure,the antibody can be glycosylated or can be non-glycosylated, withglycosylated preferred. Such methods are described in many standardlaboratory manuals, such as Sambrook, supra, Sections 17.37-17.42;Ausubel, supra, Chapters 10, 12, 13, 16, 18 and 20, Colligan, ProteinScience, supra, Chapters 12-14, all entirely incorporated herein byreference.

Anti-IL-23 Antibodies.

An anti-IL-23 antibody according to the present invention includes anyprotein or peptide containing molecule that comprises at least a portionof an immunoglobulin molecule, such as but not limited to, at least oneligand binding portion (LBP), such as but not limited to, acomplementarity determining region (CDR) of a heavy or light chain or aligand binding portion thereof, a heavy chain or light chain variableregion, a framework region (e.g., FR1, FR2, FR3, FR4 or fragmentthereof, further optionally comprising at least one substitution,insertion or deletion), a heavy chain or light chain constant region,(e.g., comprising at least one C_(H)1, hinge1, hinge2, hinge3, hinge4,C_(H)2, or C_(H)3 or fragment thereof, further optionally comprising atleast one substitution, insertion or deletion), or any portion thereof,that can be incorporated into an antibody. An antibody can include or bederived from any mammal, such as but not limited to, a human, a mouse, arabbit, a rat, a rodent, a primate, or any combination thereof, and thelike.

The isolated antibodies used in the method of the present inventioncomprise the antibody amino acid sequences disclosed herein encoded byany suitable polynucleotide, or any isolated or prepared antibody.Preferably, the human antibody or antigen-binding fragment binds humanIL-23 and, thereby, partially or substantially neutralizes at least onebiological activity of the protein. An antibody, or specified portion orvariant thereof, that partially or preferably substantially neutralizesat least one biological activity of at least one IL-23 protein orfragment can bind the protein or fragment and thereby inhibit activitiesmediated through the binding of IL-23 to the IL-23 receptor or throughother IL-23-dependent or mediated mechanisms. As used herein, the term“neutralizing antibody” refers to an antibody that can inhibit anIL-23-dependent activity by about 20-120%, preferably by at least about10, 20, 30, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95,96, 97, 98, 99, 100% or more depending on the assay. The capacity of ananti-IL-23 antibody to inhibit an IL-23-dependent activity is preferablyassessed by at least one suitable IL-23 protein or receptor assay, asdescribed herein and/or as known in the art. A human antibody can be ofany class (IgG, IgA, IgM, IgE, IgD, etc.) or isotype and can comprise akappa or lambda light chain. In one embodiment, the human antibodycomprises an IgG heavy chain or defined fragment, for example, at leastone of isotypes, IgG1, IgG2, IgG3 or IgG4 (e.g., γ1, γ2, γ3, γ4).Antibodies of this type can be prepared by employing a transgenic mouseor other trangenic non-human mammal comprising at least one human lightchain (e.g., IgG, IgA, and IgM) transgenes as described herein and/or asknown in the art. In another embodiment, the anti-IL-23 human antibodycomprises an IgG1 heavy chain and an IgG1 light chain.

An antibody binds at least one specified epitope specific to at leastone IL-23 protein, subunit, fragment, portion or any combinationthereof. The at least one epitope can comprise at least one antibodybinding region that comprises at least one portion of the protein, whichepitope is preferably comprised of at least one extracellular, soluble,hydrophillic, external or cytoplasmic portion of the protein.

Generally, the human antibody or antigen-binding fragment will comprisean antigen-binding region that comprises at least one humancomplementarity determining region (CDR1, CDR2 and CDR3) or variant ofat least one heavy chain variable region and at least one humancomplementarity determining region (CDR1, CDR2 and CDR3) or variant ofat least one light chain variable region. The CDR sequences may bederived from human germline sequences or closely match the germlinesequences. For example, the CDRs from a synthetic library derived fromthe original non-human CDRs can be used. These CDRs may be formed byincorporation of conservative substitutions from the original non-humansequence. In another particular embodiment, the antibody orantigen-binding portion or variant can have an antigen-binding regionthat comprises at least a portion of at least one light chain CDR (i.e.,CDR1, CDR2 and/or CDR3) having the amino acid sequence of thecorresponding CDRs 1, 2 and/or 3.

Such antibodies can be prepared by chemically joining together thevarious portions (e.g., CDRs, framework) of the antibody usingconventional techniques, by preparing and expressing a (i.e., one ormore) nucleic acid molecule that encodes the antibody using conventionaltechniques of recombinant DNA technology or by using any other suitablemethod.

The anti-IL-23 specific antibody can comprise at least one of a heavy orlight chain variable region having a defined amino acid sequence. Forexample, in a preferred embodiment, the anti-IL-23 antibody comprises atleast one of at least one heavy chain variable region, optionally havingthe amino acid sequence of SEQ ID NO:106 and/or at least one light chainvariable region, optionally having the amino acid sequence of SEQ IDNO:116. Antibodies that bind to human IL-23 and that comprise a definedheavy or light chain variable region can be prepared using suitablemethods, such as phage display (Katsube, Y., et al., Int J Mol. Med,1(5):863-868 (1998)) or methods that employ transgenic animals, as knownin the art and/or as described herein. For example, a transgenic mouse,comprising a functionally rearranged human immunoglobulin heavy chaintransgene and a transgene comprising DNA from a human immunoglobulinlight chain locus that can undergo functional rearrangement, can beimmunized with human IL-23 or a fragment thereof to elicit theproduction of antibodies. If desired, the antibody producing cells canbe isolated and hybridomas or other immortalized antibody-producingcells can be prepared as described herein and/or as known in the art.Alternatively, the antibody, specified portion or variant can beexpressed using the encoding nucleic acid or portion thereof in asuitable host cell.

The invention also relates to antibodies, antigen-binding fragments,immunoglobulin chains and CDRs comprising amino acids in a sequence thatis substantially the same as an amino acid sequence described herein.Preferably, such antibodies or antigen-binding fragments and antibodiescomprising such chains or CDRs can bind human IL-23 with high affinity(e.g., K_(D) less than or equal to about 10⁻⁹M). Amino acid sequencesthat are substantially the same as the sequences described hereininclude sequences comprising conservative amino acid substitutions, aswell as amino acid deletions and/or insertions. A conservative aminoacid substitution refers to the replacement of a first amino acid by asecond amino acid that has chemical and/or physical properties (e.g.,charge, structure, polarity, hydrophobicity/hydrophilicity) that aresimilar to those of the first amino acid. Conservative substitutionsinclude, without limitation, replacement of one amino acid by anotherwithin the following groups: lysine (K), arginine (R) and histidine (H);aspartate (D) and glutamate (E); asparagine (N), glutamine (Q), serine(S), threonine (T), tyrosine (Y), K, R, H, D and E; alanine (A), valine(V), leucine (L), isoleucine (I), proline (P), phenylalanine (F),tryptophan (W), methionine (M), cysteine (C) and glycine (G); F, W andY; C, S and T.

Amino Acid Codes

The amino acids that make up anti-IL-23 antibodies of the presentinvention are often abbreviated. The amino acid designations can beindicated by designating the amino acid by its single letter code, itsthree letter code, name, or three nucleotide codon(s) as is wellunderstood in the art (see Alberts, B., et al., Molecular Biology of TheCell, Third Ed., Garland Publishing, Inc., New York, 1994):

SINGLE THREE THREE LETTER LETTER NUCLEOTIDE CODE CODE NAME CODON(S) AAla Alanine GCA, GCC, GCG, GCU C Cys Cysteine UGC, UGU D Asp Asparticacid GAC, GAU E Glu Glutamic acid GAA, GAG F Phe Phenylanine UUC, UUU GGly Glycine GGA, GGC, GGG, GGU H His Histidine CAC, CAU I Ile IsoleucineAUA, AUC, AUU K Lys Lysine AAA, AAG L Leu Leucine UUA, UUG, CUA, CUC,CUG, CUU M Met Methionine AUG N Asn Asparagine AAC, AAU P Pro ProlineCCA, CCC, CCG, CCU Q Gln Glutamine CAA, CAG R Arg Arginine AGA, AGG,CGA, CGC, CGG, CGU S Ser Serine AGC, AGU, UCA, UCC, UCG, UCU T ThrThreonine ACA, ACC, ACG, ACU V Val Valine GUA, GUC, GUG, GUU W TrpTryptophan UGG Y Tyr Tyrosine UAC, UAUAn anti-IL-23 antibody used in the method of the present invention caninclude one or more amino acid substitutions, deletions or additions,either from natural mutations or human manipulation, as specifiedherein.

The number of amino acid substitutions a skilled artisan would makedepends on many factors, including those described above. Generallyspeaking, the number of amino acid substitutions, insertions ordeletions for any given anti-IL-23 antibody, fragment or variant willnot be more than 40, 30, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9,8, 7, 6, 5, 4, 3, 2, 1, such as 1-30 or any range or value therein, asspecified herein.

Amino acids in an anti-IL-23 specific antibody that are essential forfunction can be identified by methods known in the art, such assite-directed mutagenesis or alanine-scanning mutagenesis (e.g.,Ausubel, supra, Chapters 8, 15; Cunningham and Wells, Science244:1081-1085 (1989)). The latter procedure introduces single alaninemutations at every residue in the molecule. The resulting mutantmolecules are then tested for biological activity, such as, but notlimited to, at least one IL-23 neutralizing activity. Sites that arecritical for antibody binding can also be identified by structuralanalysis, such as crystallization, nuclear magnetic resonance orphotoaffinity labeling (Smith, et al., J. Mol. Biol. 224:899-904 (1992)and de Vos, et al., Science 255:306-312 (1992)).

Anti-IL-23 antibodies can include, but are not limited to, at least oneportion, sequence or combination selected from 5 to all of thecontiguous amino acids of at least one of SEQ ID NOS: 5, 20, 44, 50, 56,and 73.

IL-23 antibodies or specified portions or variants can include, but arenot limited to, at least one portion, sequence or combination selectedfrom at least 3-5 contiguous amino acids of the SEQ ID NOs above; 5-17contiguous amino acids of the SEQ ID NOs above, 5-10 contiguous aminoacids of the SEQ ID NOs above, 5-11 contiguous amino acids of the SEQ IDNOs above, 5-7 contiguous amino acids of the SEQ ID NOs above; 5-9contiguous amino acids of the SEQ ID NOs above.

An anti-IL-23 antibody can further optionally comprise a polypeptide ofat least one of 70-100% of 5, 17, 10, 11, 7, 9, 119, or 108 contiguousamino acids of the SEQ ID NOs above. In one embodiment, the amino acidsequence of an immunoglobulin chain, or portion thereof (e.g., variableregion, CDR) has about 70-100% identity (e.g., 70, 71, 72, 73, 74, 75,76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93,94, 95, 96, 97, 98, 99, 100 or any range or value therein) to the aminoacid sequence of the corresponding chain of at least one of the SEQ IDNOs above. For example, the amino acid sequence of a light chainvariable region can be compared with the sequence of the SEQ ID NOsabove, or the amino acid sequence of a heavy chain CDR3 can be comparedwith the SEQ ID NOs above. Preferably, 70-100% amino acid identity(i.e., 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or any range or valuetherein) is determined using a suitable computer algorithm, as known inthe art.

“Identity,” as known in the art, is a relationship between two or morepolypeptide sequences or two or more polynucleotide sequences, asdetermined by comparing the sequences. In the art, “identity” also meansthe degree of sequence relatedness between polypeptide or polynucleotidesequences, as determined by the match between strings of such sequences.“Identity” and “similarity” can be readily calculated by known methods,including, but not limited to, those described in ComputationalMolecular Biology, Lesk, A. M., ed., Oxford University Press, New York,1988; Biocomputing:Informatics and Genome Projects, Smith, D. W., ed.,Academic Press, New York, 1993; Computer Analysis of Sequence Data, PartI, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey,1994; Sequence Analysis in Molecular Biology, von Heinje, G., AcademicPress, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereux,J., eds., M Stockton Press, New York, 1991; and Carillo, H., and Lipman,D., Siam J. Applied Math., 48:1073 (1988). In addition, values forpercentage identity can be obtained from amino acid and nucleotidesequence alignments generated using the default settings for the AlignXcomponent of Vector NTI Suite 8.0 (Informax, Frederick, Md.).

Preferred methods to determine identity are designed to give the largestmatch between the sequences tested. Methods to determine identity andsimilarity are codified in publicly available computer programs.Preferred computer program methods to determine identity and similaritybetween two sequences include, but are not limited to, the GCG programpackage (Devereux, J., et al., Nucleic Acids Research 12(1): 387(1984)), BLASTP, BLASTN, and FASTA (Atschul, S. F. et al., J. Molec.Biol. 215:403-410 (1990)). The BLAST X program is publicly availablefrom NCBI and other sources (BLAST Manual, Altschul, S., et al., NCBINLMNIH Bethesda, Md. 20894: Altschul, S., et al., J. Mol. Biol. 215:403-410(1990). The well-known Smith Waterman algorithm may also be used todetermine identity.

Preferred parameters for polypeptide sequence comparison include thefollowing: (1) Algorithm: Needleman and Wunsch, J. Mol Biol. 48:443-453(1970) Comparison matrix: BLOSSUM62 from Hentikoff and Hentikoff, Proc.Natl. Acad. Sci, USA. 89:10915-10919 (1992)

Gap Penalty: 12 Gap Length Penalty: 4

A program useful with these parameters is publicly available as the“gap” program from Genetics Computer Group, Madison Wis. Theaforementioned parameters are the default parameters for peptidesequence comparisons (along with no penalty for end gaps).

Preferred parameters for polynucleotide comparison include thefollowing:

(1) Algorithm: Needleman and Wunsch, J. Mol Biol. 48:443-453 (1970)

Comparison matrix: matches=+10, mismatch=0

Gap Penalty: 50 Gap Length Penalty: 3

Available as: The “gap” program from Genetics Computer Group, MadisonWis. These are the default parameters for nucleic acid sequencecomparisons.

By way of example, a polynucleotide sequence may be identical to anothersequence, that is 100% identical, or it may include up to a certaininteger number of nucleotide alterations as compared to the referencesequence. Such alterations are selected from the group consisting of atleast one nucleotide deletion, substitution, including transition andtransversion, or insertion, and wherein the alterations may occur at the5′ or 3′ terminal positions of the reference nucleotide sequence oranywhere between those terminal positions, interspersed eitherindividually among the nucleotides in the reference sequence or in oneor more contiguous groups within the reference sequence. The number ofnucleotide alterations is determined by multiplying the total number ofnucleotides in the sequence by the numerical percent of the respectivepercent identity (divided by 100) and subtracting that product from thetotal number of nucleotides in the sequence, or:

n.sub.n.ltorsim.x.sub.n-(x.sub.n.y),wherein n.sub.n is the number of nucleotide alterations, x.sub.n is thetotal number of nucleotides in sequence, and y is, for instance, 0.70for 70%, 0.80 for 80%, 0.85 for 85%, 0.90 for 90%, 0.95 for 95%, etc.,and wherein any non-integer product of x.sub.n and y is rounded down tothe nearest integer prior to subtracting from x.sub.n.

Alterations of a polynucleotide sequence encoding the the SEQ ID NOsabove may create nonsense, missense or frameshift mutations in thiscoding sequence and thereby alter the polypeptide encoded by thepolynucleotide following such alterations. Similarly, a polypeptidesequence may be identical to the reference sequence of the SEQ ID NOsabove, that is be 100% identical, or it may include up to a certaininteger number of amino acid alterations as compared to the referencesequence such that the percentage identity is less than 100%. Suchalterations are selected from the group consisting of at least one aminoacid deletion, substitution, including conservative and non-conservativesubstitution, or insertion, and wherein the alterations may occur at theamino- or carboxy-terminal positions of the reference polypeptidesequence or anywhere between those terminal positions, interspersedeither individually among the amino acids in the reference sequence orin one or more contiguous groups within the reference sequence. Thenumber of amino acid alterations for a given % identity is determined bymultiplying the total number of amino acids in the SEQ ID NOs above bythe numerical percent of the respective percent identity (divided by100) and then subtracting that product from the total number of aminoacids in the SEQ ID NOs above, or:

n.sub.a.ltorsim.x.sub.a-(x.sub.a.y),wherein n.sub.a is the number of amino acid alterations, x.sub.a is thetotal number of amino acids in the SEQ ID NOs above, and y is, forinstance 0.70 for 70%, 0.80 for 80%, 0.85 for 85% etc., and wherein anynon-integer produce of x.sub.a and y is rounded down to the nearestinteger prior to subtracting it from x.sub.a.

Exemplary heavy chain and light chain variable regions sequences andportions thereof are provided in the SEQ ID NOs above. The antibodies ofthe present invention, or specified variants thereof, can comprise anynumber of contiguous amino acid residues from an antibody of the presentinvention, wherein that number is selected from the group of integersconsisting of from 10-100% of the number of contiguous residues in ananti-IL-23 antibody. Optionally, this subsequence of contiguous aminoacids is at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110,120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250 ormore amino acids in length, or any range or value therein. Further, thenumber of such subsequences can be any integer selected from the groupconsisting of from 1 to 20, such as at least 2, 3, 4, or 5.

As those of skill will appreciate, the present invention includes atleast one biologically active antibody of the present invention.Biologically active antibodies have a specific activity at least 20%,30%, or 40%, and, preferably, at least 50%, 60%, or 70%, and, mostpreferably, at least 80%, 90%, or 95%-100% or more (including, withoutlimitation, up to 10 times the specific activity) of that of the native(non-synthetic), endogenous or related and known antibody. Methods ofassaying and quantifying measures of enzymatic activity and substratespecificity are well known to those of skill in the art.

In another aspect, the invention relates to human antibodies andantigen-binding fragments, as described herein, which are modified bythe covalent attachment of an organic moiety. Such modification canproduce an antibody or antigen-binding fragment with improvedpharmacokinetic properties (e.g., increased in vivo serum half-life).The organic moiety can be a linear or branched hydrophilic polymericgroup, fatty acid group, or fatty acid ester group. In particularembodiments, the hydrophilic polymeric group can have a molecular weightof about 800 to about 120,000 Daltons and can be a polyalkane glycol(e.g., polyethylene glycol (PEG), polypropylene glycol (PPG)),carbohydrate polymer, amino acid polymer or polyvinyl pyrolidone, andthe fatty acid or fatty acid ester group can comprise from about eightto about forty carbon atoms.

The modified antibodies and antigen-binding fragments can comprise oneor more organic moieties that are covalently bonded, directly orindirectly, to the antibody. Each organic moiety that is bonded to anantibody or antigen-binding fragment of the invention can independentlybe a hydrophilic polymeric group, a fatty acid group or a fatty acidester group. As used herein, the term “fatty acid” encompassesmono-carboxylic acids and di-carboxylic acids. A “hydrophilic polymericgroup,” as the term is used herein, refers to an organic polymer that ismore soluble in water than in octane. For example, polylysine is moresoluble in water than in octane. Thus, an antibody modified by thecovalent attachment of polylysine is encompassed by the invention.Hydrophilic polymers suitable for modifying antibodies of the inventioncan be linear or branched and include, for example, polyalkane glycols(e.g., PEG, monomethoxy-polyethylene glycol (mPEG), PPG and the like),carbohydrates (e.g., dextran, cellulose, oligosaccharides,polysaccharides and the like), polymers of hydrophilic amino acids(e.g., polylysine, polyarginine, polyaspartate and the like), polyalkaneoxides (e.g., polyethylene oxide, polypropylene oxide and the like) andpolyvinyl pyrolidone. Preferably, the hydrophilic polymer that modifiesthe antibody of the invention has a molecular weight of about 800 toabout 150,000 Daltons as a separate molecular entity. For example,PEG₅₀₀₀ and PEG_(20,000), wherein the subscript is the average molecularweight of the polymer in Daltons, can be used. The hydrophilic polymericgroup can be substituted with one to about six alkyl, fatty acid orfatty acid ester groups. Hydrophilic polymers that are substituted witha fatty acid or fatty acid ester group can be prepared by employingsuitable methods. For example, a polymer comprising an amine group canbe coupled to a carboxylate of the fatty acid or fatty acid ester, andan activated carboxylate (e.g., activated with N, N-carbonyldiimidazole) on a fatty acid or fatty acid ester can be coupled to ahydroxyl group on a polymer.

Fatty acids and fatty acid esters suitable for modifying antibodies ofthe invention can be saturated or can contain one or more units ofunsaturation. Fatty acids that are suitable for modifying antibodies ofthe invention include, for example, n-dodecanoate (Cu, laurate),n-tetradecanoate (C₁₄, myristate), n-octadecanoate (C₁₈, stearate),n-eicosanoate (C₂₀, arachidate), n-docosanoate (C₂₂, behenate),n-triacontanoate (C₃₀), n-tetracontanoate (C₄₀), cis-Δ9-octadecanoate(C₁₈, oleate), all cis-Δ5,8,11,14-eicosatetraenoate (C₂₀, arachidonate),octanedioic acid, tetradecanedioic acid, octadecanedioic acid,docosanedioic acid, and the like. Suitable fatty acid esters includemono-esters of dicarboxylic acids that comprise a linear or branchedlower alkyl group. The lower alkyl group can comprise from one to abouttwelve, preferably, one to about six, carbon atoms.

The modified human antibodies and antigen-binding fragments can beprepared using suitable methods, such as by reaction with one or moremodifying agents. A “modifying agent” as the term is used herein, refersto a suitable organic group (e.g., hydrophilic polymer, a fatty acid, afatty acid ester) that comprises an activating group. An “activatinggroup” is a chemical moiety or functional group that can, underappropriate conditions, react with a second chemical group therebyforming a covalent bond between the modifying agent and the secondchemical group. For example, amine-reactive activating groups includeelectrophilic groups, such as tosylate, mesylate, halo (chloro, bromo,fluoro, iodo), N-hydroxysuccinimidyl esters (NHS), and the like.Activating groups that can react with thiols include, for example,maleimide, iodoacetyl, acrylolyl, pyridyl disulfides,5-thiol-2-nitrobenzoic acid thiol (TNB-thiol), and the like. An aldehydefunctional group can be coupled to amine- or hydrazide-containingmolecules, and an azide group can react with a trivalent phosphorousgroup to form phosphoramidate or phosphorimide linkages. Suitablemethods to introduce activating groups into molecules are known in theart (see for example, Hermanson, G. T., Bioconjugate Techniques,Academic Press: San Diego, Calif. (1996)). An activating group can bebonded directly to the organic group (e.g., hydrophilic polymer, fattyacid, fatty acid ester), or through a linker moiety, for example, adivalent C₁-C₁₂ group wherein one or more carbon atoms can be replacedby a heteroatom, such as oxygen, nitrogen or sulfur. Suitable linkermoieties include, for example, tetraethylene glycol, —(CH₂)₃—,—NH—(CH₂)₆—NH—, —(CH₂)₂—NH— and —CH₂—O—CH₂—CH₂—O—CH₂—CH₂—O—CH—NH—.Modifying agents that comprise a linker moiety can be produced, forexample, by reacting a mono-Boc-alkyldiamine (e.g.,mono-Boc-ethylenediamine, mono-Boc-diaminohexane) with a fatty acid inthe presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) toform an amide bond between the free amine and the fatty acidcarboxylate. The Boc protecting group can be removed from the product bytreatment with trifluoroacetic acid (TFA) to expose a primary amine thatcan be coupled to another carboxylate, as described, or can be reactedwith maleic anhydride and the resulting product cyclized to produce anactivated maleimido derivative of the fatty acid. (See, for example,Thompson, et al., WO 92/16221, the entire teachings of which areincorporated herein by reference.)

The modified antibodies can be produced by reacting a human antibody orantigen-binding fragment with a modifying agent. For example, theorganic moieties can be bonded to the antibody in a non-site specificmanner by employing an amine-reactive modifying agent, for example, anNHS ester of PEG. Modified human antibodies or antigen-binding fragmentscan also be prepared by reducing disulfide bonds (e.g., intra-chaindisulfide bonds) of an antibody or antigen-binding fragment. The reducedantibody or antigen-binding fragment can then be reacted with athiol-reactive modifying agent to produce the modified antibody of theinvention. Modified human antibodies and antigen-binding fragmentscomprising an organic moiety that is bonded to specific sites of anantibody of the present invention can be prepared using suitablemethods, such as reverse proteolysis (Fisch et al., Bioconjugate Chem.,3:147-153 (1992); Werlen et al., Bioconjugate Chem., 5:411-417 (1994);Kumaran et al., Protein Sci. 6(10):2233-2241 (1997); Itoh et al.,Bioorg. Chem., 24(1): 59-68 (1996); Capellas et al., Biotechnol.Bioeng., 56(4):456-463 (1997)), and the methods described in Hermanson,G. T., Bioconjugate Techniques, Academic Press: San Diego, Calif.(1996).

The method of the present invention also uses an anti-IL-23 antibodycomposition comprising at least one, at least two, at least three, atleast four, at least five, at least six or more anti-IL-23 antibodiesthereof, as described herein and/or as known in the art that areprovided in a non-naturally occurring composition, mixture or form. Suchcompositions comprise non-naturally occurring compositions comprising atleast one or two full length, C- and/or N-terminally deleted variants,domains, fragments, or specified variants, of the anti-IL-23 antibodyamino acid sequence selected from the group consisting of 70-100% of thecontiguous amino acids of the SEQ ID NOs above, or specified fragments,domains or variants thereof. Preferred anti-IL-23 antibody compositionsinclude at least one or two full length, fragments, domains or variantsas at least one CDR or LBP containing portions of the anti-IL-23antibody sequence described herein, for example, 70-100% of the SEQ IDNOs above, or specified fragments, domains or variants thereof. Furtherpreferred compositions comprise, for example, 40-99% of at least one of70-100% of the SEQ ID NOs above, etc., or specified fragments, domainsor variants thereof. Such composition percentages are by weight, volume,concentration, molarity, or molality as liquid or dry solutions,mixtures, suspension, emulsions, particles, powder, or colloids, asknown in the art or as described herein.

Antibody Compositions Comprising Further Therapeutically ActiveIngredients

The antibody compositions used in the method of the invention canoptionally further comprise an effective amount of at least one compoundor protein selected from at least one of an anti-infective drug, acardiovascular (CV) system drug, a central nervous system (CNS) drug, anautonomic nervous system (ANS) drug, a respiratory tract drug, agastrointestinal (GI) tract drug, a hormonal drug, a drug for fluid orelectrolyte balance, a hematologic drug, an antineoplastic, animmunomodulation drug, an ophthalmic, otic or nasal drug, a topicaldrug, a nutritional drug or the like. Such drugs are well known in theart, including formulations, indications, dosing and administration foreach presented herein (see, e.g., Nursing 2001 Handbook of Drugs,21^(st) edition, Springhouse Corp., Springhouse, P A, 2001; HealthProfessional's Drug Guide 2001, ed., Shannon, Wilson, Stang,Prentice-Hall, Inc, Upper Saddle River, N.J.; Pharmcotherapy Handbook,Wells et al., ed., Appleton & Lange, Stamford, Conn., each entirelyincorporated herein by reference).

By way of example of the drugs that can be combined with the antibodiesfor the method of the present invention, the anti-infective drug can beat least one selected from amebicides or at least one antiprotozoals,anthelmintics, antifungals, antimalarials, antituberculotics or at leastone antileprotics, aminoglycosides, penicillins, cephalosporins,tetracyclines, sulfonamides, fluoroquinolones, antivirals, macrolideanti-infectives, and miscellaneous anti-infectives. The hormonal drugcan be at least one selected from corticosteroids, androgens or at leastone anabolic steroid, estrogen or at least one progestin, gonadotropin,antidiabetic drug or at least one glucagon, thyroid hormone, thyroidhormone antagonist, pituitary hormone, and parathyroid-like drug. The atleast one cephalosporin can be at least one selected from cefaclor,cefadroxil, cefazolin sodium, cefdinir, cefepime hydrochloride,cefixime, cefmetazole sodium, cefonicid sodium, cefoperazone sodium,cefotaxime sodium, cefotetan disodium, cefoxitin sodium, cefpodoximeproxetil, cefprozil, ceftazidime, ceftibuten, ceftizoxime sodium,ceftriaxone sodium, cefuroxime axetil, cefuroxime sodium, cephalexinhydrochloride, cephalexin monohydrate, cephradine, and loracarbef.

The at least one coricosteroid can be at least one selected frombetamethasone, betamethasone acetate or betamethasone sodium phosphate,betamethasone sodium phosphate, cortisone acetate, dexamethasone,dexamethasone acetate, dexamethasone sodium phosphate, fludrocortisoneacetate, hydrocortisone, hydrocortisone acetate, hydrocortisonecypionate, hydrocortisone sodium phosphate, hydrocortisone sodiumsuccinate, methylprednisolone, methylprednisolone acetate,methylprednisolone sodium succinate, prednisolone, prednisolone acetate,prednisolone sodium phosphate, prednisolone tebutate, prednisone,triamcinolone, triamcinolone acetonide, and triamcinolone diacetate. Theat least one androgen or anabolic steroid can be at least one selectedfrom danazol, fluoxymesterone, methyltestosterone, nandrolone decanoate,nandrolone phenpropionate, testosterone, testosterone cypionate,testosterone enanthate, testosterone propionate, and testosteronetransdermal system.

The at least one immunosuppressant can be at least one selected fromazathioprine, basiliximab, cyclosporine, daclizumab, lymphocyte immuneglobulin, muromonab-CD3, mycophenolate mofetil, mycophenolate mofetilhydrochloride, sirolimus, and tacrolimus.

The at least one local anti-infective can be at least one selected fromacyclovir, amphotericin B, azelaic acid cream, bacitracin, butoconazolenitrate, clindamycin phosphate, clotrimazole, econazole nitrate,erythromycin, gentamicin sulfate, ketoconazole, mafenide acetate,metronidazole (topical), miconazole nitrate, mupirocin, naftifinehydrochloride, neomycin sulfate, nitrofurazone, nystatin, silversulfadiazine, terbinafine hydrochloride, terconazole, tetracyclinehydrochloride, tioconazole, and tolnaftate. The at least one scabicideor pediculicide can be at least one selected from crotamiton, lindane,permethrin, and pyrethrins. The at least one topical corticosteroid canbe at least one selected from betamethasone dipropionate, betamethasonevalerate, clobetasol propionate, desonide, desoximetasone,dexamethasone, dexamethasone sodium phosphate, diflorasone diacetate,fluocinolone acetonide, fluocinonide, flurandrenolide, fluticasonepropionate, halcionide, hydrocortisone, hydrocortisone acetate,hydrocortisone butyrate, hydrocorisone valerate, mometasone furoate, andtriamcinolone acetonide. (See, e.g., pp. 1098-1136 of Nursing 2001 DrugHandbook.)

Anti-IL-23 antibody compositions can further comprise at least one ofany suitable and effective amount of a composition or pharmaceuticalcomposition comprising at least one anti-IL-23 antibody contacted oradministered to a cell, tissue, organ, animal or patient in need of suchmodulation, treatment or therapy, optionally further comprising at leastone selected from at least one TNF antagonist (e.g., but not limited toa TNF chemical or protein antagonist, TNF monoclonal or polyclonalantibody or fragment, a soluble TNF receptor (e.g., p55, p70 or p85) orfragment, fusion polypeptides thereof, or a small molecule TNFantagonist, e.g., TNF binding protein I or II (TBP-1 or TBP-II),nerelimonmab, infliximab, eternacept, CDP-571, CDP-870, afelimomab,lenercept, and the like), an antirheumatic (e.g., methotrexate,auranofin, aurothioglucose, azathioprine, etanercept, gold sodiumthiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalzine), animmunization, an immunoglobulin, an immunosuppressive (e.g.,basiliximab, cyclosporine, daclizumab), a cytokine or a cytokineantagonist. Non-limiting examples of such cytokines include, but are notlimited to, any of IL-1 to IL-23 et al. (e.g., IL-1, IL-2, etc.).Suitable dosages are well known in the art. See, e.g., Wells et al.,eds., Pharmacotherapy Handbook, 2^(nd) Edition, Appleton and Lange,Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000),each of which references are entirely incorporated herein by reference.

Anti-IL-23 antibody compounds, compositions or combinations used in themethod of the present invention can further comprise at least one of anysuitable auxiliary, such as, but not limited to, diluent, binder,stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvantor the like. Pharmaceutically acceptable auxiliaries are preferred.Non-limiting examples of, and methods of preparing such sterilesolutions are well known in the art, such as, but limited to, Gennaro,Ed., Remington's Pharmaceutical Sciences, 18^(th) Edition, MackPublishing Co. (Easton, Pa.) 1990. Pharmaceutically acceptable carrierscan be routinely selected that are suitable for the mode ofadministration, solubility and/or stability of the anti-IL-23 antibody,fragment or variant composition as well known in the art or as describedherein.

Pharmaceutical excipients and additives useful in the presentcomposition include, but are not limited to, proteins, peptides, aminoacids, lipids, and carbohydrates (e.g., sugars, includingmonosaccharides, di-, tri-, tetra-, and oligosaccharides; derivatizedsugars, such as alditols, aldonic acids, esterified sugars and the like;and polysaccharides or sugar polymers), which can be present singly orin combination, comprising alone or in combination 1-99.99% by weight orvolume. Exemplary protein excipients include serum albumin, such ashuman serum albumin (HSA), recombinant human albumin (rHA), gelatin,casein, and the like. Representative amino acid/antibody components,which can also function in a buffering capacity, include alanine,glycine, arginine, betaine, histidine, glutamic acid, aspartic acid,cysteine, lysine, leucine, isoleucine, valine, methionine,phenylalanine, aspartame, and the like. One preferred amino acid isglycine.

Carbohydrate excipients suitable for use in the invention include, forexample, monosaccharides, such as fructose, maltose, galactose, glucose,D-mannose, sorbose, and the like; disaccharides, such as lactose,sucrose, trehalose, cellobiose, and the like; polysaccharides, such asraffinose, melezitose, maltodextrins, dextrans, starches, and the like;and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitolsorbitol (glucitol), myoinositol and the like. Preferred carbohydrateexcipients for use in the present invention are mannitol, trehalose, andraffinose.

Anti-IL-23 antibody compositions can also include a buffer or a pHadjusting agent; typically, the buffer is a salt prepared from anorganic acid or base. Representative buffers include organic acid salts,such as salts of citric acid, ascorbic acid, gluconic acid, carbonicacid, tartaric acid, succinic acid, acetic acid, or phthalic acid; Tris,tromethamine hydrochloride, or phosphate buffers. Preferred buffers foruse in the present compositions are organic acid salts, such as citrate.

Additionally, anti-IL-23 antibody compositions can include polymericexcipients/additives, such as polyvinylpyrrolidones, ficolls (apolymeric sugar), dextrates (e.g., cyclodextrins, such as2-hydroxypropyl-β-cyclodextrin), polyethylene glycols, flavoring agents,antimicrobial agents, sweeteners, antioxidants, antistatic agents,surfactants (e.g., polysorbates, such as “TWEEN 20” and “TWEEN 80”),lipids (e.g., phospholipids, fatty acids), steroids (e.g., cholesterol),and chelating agents (e.g., EDTA).

These and additional known pharmaceutical excipients and/or additivessuitable for use in the anti-IL-23 antibody, portion or variantcompositions according to the invention are known in the art, e.g., aslisted in “Remington: The Science & Practice of Pharmacy,” 19^(th) ed.,Williams & Williams, (1995), and in the “Physician's Desk Reference,”52^(nd) ed., Medical Economics, Montvale, N.J. (1998), the disclosuresof which are entirely incorporated herein by reference. Preferredcarrier or excipient materials are carbohydrates (e.g., saccharides andalditols) and buffers (e.g., citrate) or polymeric agents. An exemplarycarrier molecule is the mucopolysaccharide, hyaluronic acid, which maybe useful for intraarticular delivery.

Formulations

As noted above, the invention provides for stable formulations, whichpreferably comprise a phosphate buffer with saline or a chosen salt, aswell as preserved solutions and formulations containing a preservativeas well as multi-use preserved formulations suitable for pharmaceuticalor veterinary use, comprising at least one anti-IL-23 antibody in apharmaceutically acceptable formulation. Preserved formulations containat least one known preservative or optionally selected from the groupconsisting of at least one phenol, m-cresol, p-cresol, o-cresol,chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol,formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate),alkylparaben (methyl, ethyl, propyl, butyl and the like), benzalkoniumchloride, benzethonium chloride, sodium dehydroacetate and thimerosal,or mixtures thereof in an aqueous diluent. Any suitable concentration ormixture can be used as known in the art, such as 0.001-5%, or any rangeor value therein, such as, but not limited to 0.001, 0.003, 0.005,0.009, 0.01, 0.02, 0.03, 0.05, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7,0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1,2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5,3.6, 3.7, 3.8, 3.9, 4.0, 4.3, 4.5, 4.6, 4.7, 4.8, 4.9, or any range orvalue therein. Non-limiting examples include, no preservative, 0.1-2%m-cresol (e.g., 0.2, 0.3. 0.4, 0.5, 0.9, 1.0%), 0.1-3% benzyl alcohol(e.g., 0.5, 0.9, 1.1, 1.5, 1.9, 2.0, 2.5%), 0.001-0.5% thimerosal (e.g.,0.005, 0.01), 0.001-2.0% phenol (e.g., 0.05, 0.25, 0.28, 0.5, 0.9,1.0%), 0.0005-1.0% alkylparaben(s) (e.g., 0.00075, 0.0009, 0.001, 0.002,0.005, 0.0075, 0.009, 0.01, 0.02, 0.05, 0.075, 0.09, 0.1, 0.2, 0.3, 0.5,0.75, 0.9, 1.0%), and the like.

As noted above, the method of the invention uses an article ofmanufacture, comprising packaging material and at least one vialcomprising a solution of at least one anti-IL-23 specific antibody withthe prescribed buffers and/or preservatives, optionally in an aqueousdiluent, wherein said packaging material comprises a label thatindicates that such solution can be held over a period of 1, 2, 3, 4, 5,6, 9, 12, 18, 20, 24, 30, 36, 40, 48, 54, 60, 66, 72 hours or greater.The invention further uses an article of manufacture, comprisingpackaging material, a first vial comprising lyophilized anti-IL-23specific antibody, and a second vial comprising an aqueous diluent ofprescribed buffer or preservative, wherein said packaging materialcomprises a label that instructs a patient to reconstitute theanti-IL-23 specific antibody in the aqueous diluent to form a solutionthat can be held over a period of twenty-four hours or greater.

The anti-IL-23 specific antibody used in accordance with the presentinvention can be produced by recombinant means, including from mammaliancell or transgenic preparations, or can be purified from otherbiological sources, as described herein or as known in the art.

The range of the anti-IL-23 specific antibody includes amounts yieldingupon reconstitution, if in a wet/dry system, concentrations from about1.0 μg/ml to about 1000 mg/ml, although lower and higher concentrationsare operable and are dependent on the intended delivery vehicle, e.g.,solution formulations will differ from transdermal patch, pulmonary,transmucosal, or osmotic or micro pump methods.

Preferably, the aqueous diluent optionally further comprises apharmaceutically acceptable preservative. Preferred preservativesinclude those selected from the group consisting of phenol, m-cresol,p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkylparaben (methyl,ethyl, propyl, butyl and the like), benzalkonium chloride, benzethoniumchloride, sodium dehydroacetate and thimerosal, or mixtures thereof. Theconcentration of preservative used in the formulation is a concentrationsufficient to yield an anti-microbial effect. Such concentrations aredependent on the preservative selected and are readily determined by theskilled artisan.

Other excipients, e.g., isotonicity agents, buffers, antioxidants, andpreservative enhancers, can be optionally and preferably added to thediluent. An isotonicity agent, such as glycerin, is commonly used atknown concentrations. A physiologically tolerated buffer is preferablyadded to provide improved pH control. The formulations can cover a widerange of pHs, such as from about pH 4 to about pH 10, and preferredranges from about pH 5 to about pH 9, and a most preferred range ofabout 6.0 to about 8.0. Preferably, the formulations of the presentinvention have a pH between about 6.8 and about 7.8. Preferred buffersinclude phosphate buffers, most preferably, sodium phosphate,particularly, phosphate buffered saline (PBS).

Other additives, such as a pharmaceutically acceptable solubilizers likeTween 20 (polyoxyethylene (20) sorbitan monolaurate), Tween 40(polyoxyethylene (20) sorbitan monopalmitate), Tween 80 (polyoxyethylene(20) sorbitan monooleate), Pluronic F68 (polyoxyethylenepolyoxypropylene block copolymers), and PEG (polyethylene glycol) ornon-ionic surfactants, such as polysorbate 20 or 80 or poloxamer 184 or188, Pluronic® polyls, other block co-polymers, and chelators, such asEDTA and EGTA, can optionally be added to the formulations orcompositions to reduce aggregation. These additives are particularlyuseful if a pump or plastic container is used to administer theformulation. The presence of pharmaceutically acceptable surfactantmitigates the propensity for the protein to aggregate.

The formulations can be prepared by a process which comprises mixing atleast one anti-IL-23 specific antibody and a preservative selected fromthe group consisting of phenol, m-cresol, p-cresol, o-cresol,chlorocresol, benzyl alcohol, alkylparaben, (methyl, ethyl, propyl,butyl and the like), benzalkonium chloride, benzethonium chloride,sodium dehydroacetate and thimerosal or mixtures thereof in an aqueousdiluent. Mixing the at least one anti-IL-23 specific antibody andpreservative in an aqueous diluent is carried out using conventionaldissolution and mixing procedures. To prepare a suitable formulation,for example, a measured amount of at least one anti-IL-23 specificantibody in buffered solution is combined with the desired preservativein a buffered solution in quantities sufficient to provide the proteinand preservative at the desired concentrations. Variations of thisprocess would be recognized by one of ordinary skill in the art. Forexample, the order the components are added, whether additionaladditives are used, the temperature and pH at which the formulation isprepared, are all factors that can be optimized for the concentrationand means of administration used.

The formulations can be provided to patients as clear solutions or asdual vials comprising a vial of lyophilized anti-IL-23 specific antibodythat is reconstituted with a second vial containing water, apreservative and/or excipients, preferably, a phosphate buffer and/orsaline and a chosen salt, in an aqueous diluent. Either a singlesolution vial or dual vial requiring reconstitution can be reusedmultiple times and can suffice for a single or multiple cycles ofpatient treatment and thus can provide a more convenient treatmentregimen than currently available.

The present articles of manufacture are useful for administration over aperiod ranging from immediate to twenty-four hours or greater.Accordingly, the presently claimed articles of manufacture offersignificant advantages to the patient. Formulations of the invention canoptionally be safely stored at temperatures of from about 2° C. to about40° C. and retain the biologically activity of the protein for extendedperiods of time, thus allowing a package label indicating that thesolution can be held and/or used over a period of 6, 12, 18, 24, 36, 48,72, or 96 hours or greater. If preserved diluent is used, such label caninclude use up to 1-12 months, one-half, one and a half, and/or twoyears.

The solutions of anti-IL-23 specific antibody can be prepared by aprocess that comprises mixing at least one antibody in an aqueousdiluent. Mixing is carried out using conventional dissolution and mixingprocedures. To prepare a suitable diluent, for example, a measuredamount of at least one antibody in water or buffer is combined inquantities sufficient to provide the protein and, optionally, apreservative or buffer at the desired concentrations. Variations of thisprocess would be recognized by one of ordinary skill in the art. Forexample, the order the components are added, whether additionaladditives are used, the temperature and pH at which the formulation isprepared, are all factors that can be optimized for the concentrationand means of administration used.

The claimed products can be provided to patients as clear solutions oras dual vials comprising a vial of lyophilized at least one anti-IL-23specific antibody that is reconstituted with a second vial containingthe aqueous diluent. Either a single solution vial or dual vialrequiring reconstitution can be reused multiple times and can sufficefor a single or multiple cycles of patient treatment and thus provides amore convenient treatment regimen than currently available.

The claimed products can be provided indirectly to patients by providingto pharmacies, clinics, or other such institutions and facilities, clearsolutions or dual vials comprising a vial of lyophilized at least oneanti-IL-23 specific antibody that is reconstituted with a second vialcontaining the aqueous diluent. The clear solution in this case can beup to one liter or even larger in size, providing a large reservoir fromwhich smaller portions of the at least one antibody solution can beretrieved one or multiple times for transfer into smaller vials andprovided by the pharmacy or clinic to their customers and/or patients.

Recognized devices comprising single vial systems include pen-injectordevices for delivery of a solution, such as BD Pens, BD Autojector®,Humaject®, NovoPen®, B-D® Pen, AutoPen®, and OptiPen®, GenotropinPen®,Genotronorm Pen®, Humatro Pen®, Reco-Pen®, Roferon Pen®, Biojector®,Iject®, J-tip Needle-Free Injector®, Intraject®, Medi-Ject®, Smartject®e.g., as made or developed by Becton Dickensen (Franklin Lakes, N.J.,www.bectondickenson.com), Disetronic (Burgdorf, Switzerland,www.disetronic.com; Bioject, Portland, Oreg. (www.bioject.com); NationalMedical Products, Weston Medical (Peterborough, UK,www.weston-medical.com), Medi-Ject Corp (Minneapolis, Minn.,www.mediject.com), and similary suitable devices. Recognized devicescomprising a dual vial system include those pen-injector systems forreconstituting a lyophilized drug in a cartridge for delivery of thereconstituted solution, such as the HumatroPen®. Examples of otherdevices suitable include pre-filled syringes, auto-injectors, needlefree injectors, and needle free IV infusion sets.

The products may include packaging material. The packaging materialprovides, in addition to the information required by the regulatoryagencies, the conditions under which the product can be used. Thepackaging material of the present invention provides instructions to thepatient, as applicable, to reconstitute the at least one anti-IL-23antibody in the aqueous diluent to form a solution and to use thesolution over a period of 2-24 hours or greater for the two vial,wet/dry, product. For the single vial, solution product, pre-filledsyringe or auto-injector, the label indicates that such solution can beused over a period of 2-24 hours or greater. The products are useful forhuman pharmaceutical product use.

The formulations used in the method of the present invention can beprepared by a process that comprises mixing an anti-IL-23 antibody and aselected buffer, preferably, a phosphate buffer containing saline or achosen salt. Mixing the anti-IL-23 antibody and buffer in an aqueousdiluent is carried out using conventional dissolution and mixingprocedures. To prepare a suitable formulation, for example, a measuredamount of at least one antibody in water or buffer is combined with thedesired buffering agent in water in quantities sufficient to provide theprotein and buffer at the desired concentrations. Variations of thisprocess would be recognized by one of ordinary skill in the art. Forexample, the order the components are added, whether additionaladditives are used, the temperature and pH at which the formulation isprepared, are all factors that can be optimized for the concentrationand means of administration used.

The method of the invention provides pharmaceutical compositionscomprising various formulations useful and acceptable for administrationto a human or animal patient. Such pharmaceutical compositions areprepared using water at “standard state” as the diluent and routinemethods well known to those of ordinary skill in the art. For example,buffering components such as histidine and histidine monohydrochloridehydrate, may be provided first followed by the addition of anappropriate, non-final volume of water diluent, sucrose and polysorbate80 at “standard state.” Isolated antibody may then be added. Last, thevolume of the pharmaceutical composition is adjusted to the desiredfinal volume under “standard state” conditions using water as thediluent. Those skilled in the art will recognize a number of othermethods suitable for the preparation of the pharmaceutical compositions.

The pharmaceutical compositions may be aqueous solutions or suspensionscomprising the indicated mass of each constituent per unit of watervolume or having an indicated pH at “standard state.” As used herein,the term “standard state” means a temperature of 25° C.+/−2° C. and apressure of 1 atmosphere. The term “standard state” is not used in theart to refer to a single art recognized set of temperatures or pressure,but is instead a reference state that specifies temperatures andpressure to be used to describe a solution or suspension with aparticular composition under the reference “standard state” conditions.This is because the volume of a solution is, in part, a function oftemperature and pressure. Those skilled in the art will recognize thatpharmaceutical compositions equivalent to those disclosed here can beproduced at other temperatures and pressures. Whether suchpharmaceutical compositions are equivalent to those disclosed hereshould be determined under the “standard state” conditions defined above(e.g. 25° C.+/−2° C. and a pressure of 1 atmosphere).

Importantly, such pharmaceutical compositions may contain componentmasses “about” a certain value (e.g. “about 0.53 mg L-histidine”) perunit volume of the pharmaceutical composition or have pH values about acertain value. A component mass present in a pharmaceutical compositionor pH value is “about” a given numerical value if the isolated antibodypresent in the pharmaceutical composition is able to bind a peptidechain while the isolated antibody is present in the pharmaceuticalcomposition or after the isolated antibody has been removed from thepharmaceutical composition (e.g., by dilution). Stated differently, avalue, such as a component mass value or pH value, is “about” a givennumerical value when the binding activity of the isolated antibody ismaintained and detectable after placing the isolated antibody in thepharmaceutical composition.

Competition binding analysis is performed to determine if the IL-23specific mAbs bind to similar or different epitopes and/or compete witheach other. Abs are individually coated on ELISA plates. Competing mAbsare added, followed by the addition of biotinylated hrIL-23. Forpositive control, the same mAb for coating may be used as the competingmAb (“self-competition”). IL-23 binding is detected using streptavidin.These results demonstrate whether the mAbs recognize similar orpartially overlapping epitopes on IL-23.

One aspect of the method of the invention administers to a patient apharmaceutical composition comprising

In one embodiment of the pharmaceutical compositions, the isolatedantibody concentration is from about 77 to about 104 mg per ml of thepharmaceutical composition. In another embodiment of the pharmaceuticalcompositions the pH is from about 5.5 to about 6.5.

The stable or preserved formulations can be provided to patients asclear solutions or as dual vials comprising a vial of lyophilized atleast one anti-IL-23 antibody that is reconstituted with a second vialcontaining a preservative or buffer and excipients in an aqueousdiluent. Either a single solution vial or dual vial requiringreconstitution can be reused multiple times and can suffice for a singleor multiple cycles of patient treatment and thus provides a moreconvenient treatment regimen than currently available.

Other formulations or methods of stabilizing the anti-IL-23 antibody mayresult in other than a clear solution of lyophilized powder comprisingthe antibody. Among non-clear solutions are formulations comprisingparticulate suspensions, said particulates being a compositioncontaining the anti-IL-23 antibody in a structure of variable dimensionand known variously as a microsphere, microparticle, nanoparticle,nanosphere, or liposome. Such relatively homogenous, essentiallyspherical, particulate formulations containing an active agent can beformed by contacting an aqueous phase containing the active agent and apolymer and a nonaqueous phase followed by evaporation of the nonaqueousphase to cause the coalescence of particles from the aqueous phase astaught in U.S. Pat. No. 4,589,330. Porous microparticles can be preparedusing a first phase containing active agent and a polymer dispersed in acontinuous solvent and removing said solvent from the suspension byfreeze-drying or dilution-extraction-precipitation as taught in U.S.Pat. No. 4,818,542. Preferred polymers for such preparations are naturalor synthetic copolymers or polymers selected from the group consistingof gleatin agar, starch, arabinogalactan, albumin, collagen,polyglycolic acid, polylactic aced, glycolide-L(−) lactidepoly(episilon-caprolactone, poly(epsilon-caprolactone-CO-lactic acid),poly(epsilon-caprolactone-CO-glycolic acid), poly(ß-hydroxy butyricacid), polyethylene oxide, polyethylene, poly(alkyl-2-cyanoacrylate),poly(hydroxyethyl methacrylate), polyamides, poly(amino acids),poly(2-hydroxyethyl DL-aspartamide), poly(ester urea),poly(L-phenylalanine/ethylene glycol/1,6-diisocyanatohexane) andpoly(methyl methacrylate). Particularly preferred polymers arepolyesters, such as polyglycolic acid, polylactic aced, glycolide-L(−)lactide poly(episilon-caprolactone, poly(epsilon-caprolactone-CO-lacticacid), and poly(epsilon-caprolactone-CO-glycolic acid. Solvents usefulfor dissolving the polymer and/or the active include: water,hexafluoroisopropanol, methylenechloride, tetrahydrofuran, hexane,benzene, or hexafluoroacetone sesquihydrate. The process of dispersingthe active containing phase with a second phase may include pressureforcing said first phase through an orifice in a nozzle to affectdroplet formation.

Dry powder formulations may result from processes other thanlyophilization, such as by spray drying or solvent extraction byevaporation or by precipitation of a crystalline composition followed byone or more steps to remove aqueous or nonaqueous solvent. Preparationof a spray-dried antibody preparation is taught in U.S. Pat. No.6,019,968. The antibody-based dry powder compositions may be produced byspray drying solutions or slurries of the antibody and, optionally,excipients, in a solvent under conditions to provide a respirable drypowder. Solvents may include polar compounds, such as water and ethanol,which may be readily dried. Antibody stability may be enhanced byperforming the spray drying procedures in the absence of oxygen, such asunder a nitrogen blanket or by using nitrogen as the drying gas. Anotherrelatively dry formulation is a dispersion of a plurality of perforatedmicrostructures dispersed in a suspension medium that typicallycomprises a hydrofluoroalkane propellant as taught in WO 9916419. Thestabilized dispersions may be administered to the lung of a patientusing a metered dose inhaler. Equipment useful in the commercialmanufacture of spray dried medicaments are manufactured by Buchi Ltd. orNiro Corp.

An anti-IL-23 antibody in either the stable or preserved formulations orsolutions described herein, can be administered to a patient inaccordance with the present invention via a variety of delivery methodsincluding SC or IM injection; transdermal, pulmonary, transmucosal,implant, osmotic pump, cartridge, micro pump, or other means appreciatedby the skilled artisan, as well-known in the art.

Therapeutic Applications

The present invention also provides a method for modulating or treatingpsoriasis, in a cell, tissue, organ, animal, or patient, as known in theart or as described herein, using at least one IL-23 antibody of thepresent invention, e.g., administering or contacting the cell, tissue,organ, animal, or patient with a therapeutic effective amount of IL-23specific antibody.

Any method of the present invention can comprise administering aneffective amount of a composition or pharmaceutical compositioncomprising an anti-IL-23 antibody to a cell, tissue, organ, animal orpatient in need of such modulation, treatment or therapy. Such a methodcan optionally further comprise co-administration or combination therapyfor treating such diseases or disorders, wherein the administering ofsaid at least one anti-IL-23 antibody, specified portion or variantthereof, further comprises administering, before concurrently, and/orafter, at least one selected from at least one TNF antagonist (e.g., butnot limited to, a TNF chemical or protein antagonist, TNF monoclonal orpolyclonal antibody or fragment, a soluble TNF receptor (e.g., p55, p70or p85) or fragment, fusion polypeptides thereof, or a small moleculeTNF antagonist, e.g., TNF binding protein I or II (TBP-1 or TBP-II),nerelimonmab, infliximab, eternacept (Enbrel™), adalimulab (Humira™),CDP-571, CDP-870, afelimomab, lenercept, and the like), an antirheumatic(e.g., methotrexate, auranofin, aurothioglucose, azathioprine, goldsodium thiomalate, hydroxychloroquine sulfate, leflunomide,sulfasalzine), a muscle relaxant, a narcotic, a non-steroidanti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative,a local anesthetic, a neuromuscular blocker, an antimicrobial (e.g.,aminoglycoside, an antifungal, an antiparasitic, an antiviral, acarbapenem, cephalosporin, a flurorquinolone, a macrolide, a penicillin,a sulfonamide, a tetracycline, another antimicrobial), an antipsoriatic,a corticosteriod, an anabolic steroid, a diabetes related agent, amineral, a nutritional, a thyroid agent, a vitamin, a calcium relatedhormone, an antidiarrheal, an antitussive, an antiemetic, an antiulcer,a laxative, an anticoagulant, an erythropoietin (e.g., epoetin alpha), afilgrastim (e.g., G-CSF, Neupogen), a sargramostim (GM-CSF, Leukine), animmunization, an immunoglobulin, an immunosuppressive (e.g.,basiliximab, cyclosporine, daclizumab), a growth hormone, a hormonereplacement drug, an estrogen receptor modulator, a mydriatic, acycloplegic, an alkylating agent, an antimetabolite, a mitoticinhibitor, a radiopharmaceutical, an antidepressant, antimanic agent, anantipsychotic, an anxiolytic, a hypnotic, a sympathomimetic, astimulant, donepezil, tacrine, an asthma medication, a beta agonist, aninhaled steroid, a leukotriene inhibitor, a methylxanthine, a cromolyn,an epinephrine or analog, dornase alpha (Pulmozyme), a cytokine or acytokine antagonist. Suitable dosages are well known in the art. See,e.g., Wells et al., eds., Pharmacotherapy Handbook, 2^(nd) Edition,Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, TarasconPocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, LomaLinda, Calif. (2000); Nursing 2001 Handbook of Drugs, 21^(st) edition,Springhouse Corp., Springhouse, Pa., 2001; Health Professional's DrugGuide 2001, ed., Shannon, Wilson, Stang, Prentice-Hall, Inc, UpperSaddle River, N.J., each of which references are entirely incorporatedherein by reference.

Therapeutic Treatments

Typically, treatment of psoriatic arthritis is affected by administeringan effective amount or dosage of an anti-IL-23 antibody composition thattotal, on average, a range from at least about 0.01 to 500 milligrams ofan anti-IL-23 antibody per kilogram of patient per dose, and,preferably, from at least about 0.1 to 100 milligrams antibody/kilogramof patient per single or multiple administration, depending upon thespecific activity of the active agent contained in the composition.Alternatively, the effective serum concentration can comprise 0.1-5000μg/ml serum concentration per single or multiple administrations.Suitable dosages are known to medical practitioners and will, of course,depend upon the particular disease state, specific activity of thecomposition being administered, and the particular patient undergoingtreatment. In some instances, to achieve the desired therapeutic amount,it can be necessary to provide for repeated administration, i.e.,repeated individual administrations of a particular monitored or metereddose, where the individual administrations are repeated until thedesired daily dose or effect is achieved.

Preferred doses can optionally include 0.1, 0.2, 0.3, 0.4, 0.5, 0.6,0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52,53, 54, 55, 56, 57, 58, 59, 60, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71,72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, 99 and/or 100-500mg/kg/administration, or any range, value or fraction thereof, or toachieve a serum concentration of 0.1, 0.5, 0.9, 1.0, 1.1, 1.2, 1.5, 1.9,2.0, 2.5, 2.9, 3.0, 3.5, 3.9, 4.0, 4.5, 4.9, 5.0, 5.5, 5.9, 6.0, 6.5,6.9, 7.0, 7.5, 7.9, 8.0, 8.5, 8.9, 9.0, 9.5, 9.9, 10, 10.5, 10.9, 11,11.5, 11.9, 20, 12.5, 12.9, 13.0, 13.5, 13.9, 14.0, 14.5, 4.9, 5.0,5.5., 5.9, 6.0, 6.5, 6.9, 7.0, 7.5, 7.9, 8.0, 8.5, 8.9, 9.0, 9.5, 9.9,10, 10.5, 10.9, 11, 11.5, 11.9, 12, 12.5, 12.9, 13.0, 13.5, 13.9, 14,14.5, 15, 15.5, 15.9, 16, 16.5, 16.9, 17, 17.5, 17.9, 18, 18.5, 18.9,19, 19.5, 19.9, 20, 20.5, 20.9, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 96, 100, 200, 300, 400,500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500,and/or 5000 μg/ml serum concentration per single or multipleadministration, or any range, value or fraction thereof.

Alternatively, the dosage administered can vary depending upon knownfactors, such as the pharmacodynamic characteristics of the particularagent, and its mode and route of administration; age, health, and weightof the recipient; nature and extent of symptoms, kind of concurrenttreatment, frequency of treatment, and the effect desired. Usually adosage of active ingredient can be about 0.1 to 100 milligrams perkilogram of body weight. Ordinarily 0.1 to 50, and, preferably, 0.1 to10 milligrams per kilogram per administration or in sustained releaseform is effective to obtain desired results.

As a non-limiting example, treatment of humans or animals can beprovided as a one-time or periodic dosage of at least one antibody ofthe present invention 0.1 to 100 mg/kg, such as 0.5, 0.9, 1.0, 1.1, 1.5,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90 or 100mg/kg, per day, on at least one of day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40, or, alternatively oradditionally, at least one of week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47,48, 49, 50, 51, or 52, or, alternatively or additionally, at least oneof 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or20 years, or any combination thereof, using single, infusion or repeateddoses.

Dosage forms (composition) suitable for internal administrationgenerally contain from about 0.001 milligram to about 500 milligrams ofactive ingredient per unit or container. In these pharmaceuticalcompositions the active ingredient will ordinarily be present in anamount of about 0.5-99.999% by weight based on the total weight of thecomposition.

For parenteral administration, the antibody can be formulated as asolution, suspension, emulsion, particle, powder, or lyophilized powderin association, or separately provided, with a pharmaceuticallyacceptable parenteral vehicle. Examples of such vehicles are water,saline, Ringer's solution, dextrose solution, and 1-10% human serumalbumin. Liposomes and nonaqueous vehicles, such as fixed oils, can alsobe used. The vehicle or lyophilized powder can contain additives thatmaintain isotonicity (e.g., sodium chloride, mannitol) and chemicalstability (e.g., buffers and preservatives). The formulation issterilized by known or suitable techniques.

Suitable pharmaceutical carriers are described in the most recentedition of Remington's Pharmaceutical Sciences, A. Osol, a standardreference text in this field.

Alternative Administration

Many known and developed modes can be used according to the presentinvention for administering pharmaceutically effective amounts of ananti-IL-23 antibody. While pulmonary administration is used in thefollowing description, other modes of administration can be usedaccording to the present invention with suitable results. IL-23 specificantibodies of the present invention can be delivered in a carrier, as asolution, emulsion, colloid, or suspension, or as a dry powder, usingany of a variety of devices and methods suitable for administration byinhalation or other modes described here within or known in the art.

Parenteral Formulations and Administration

Formulations for parenteral administration can contain as commonexcipients sterile water or saline, polyalkylene glycols, such aspolyethylene glycol, oils of vegetable origin, hydrogenated naphthalenesand the like. Aqueous or oily suspensions for injection can be preparedby using an appropriate emulsifier or humidifier and a suspending agent,according to known methods. Agents for injection can be a non-toxic,non-orally administrable diluting agent, such as aqueous solution, asterile injectable solution or suspension in a solvent. As the usablevehicle or solvent, water, Ringer's solution, isotonic saline, etc. areallowed; as an ordinary solvent or suspending solvent, sterileinvolatile oil can be used. For these purposes, any kind of involatileoil and fatty acid can be used, including natural or synthetic orsemisynthetic fatty oils or fatty acids; natural or synthetic orsemisynthtetic mono- or di- or tri-glycerides. Parental administrationis known in the art and includes, but is not limited to, conventionalmeans of injections, a gas pressured needle-less injection device asdescribed in U.S. Pat. No. 5,851,198, and a laser perforator device asdescribed in U.S. Pat. No. 5,839,446 entirely incorporated herein byreference.

Alternative Delivery

The invention further relates to the administration of an anti-IL-23antibody by parenteral, subcutaneous, intramuscular, intravenous,intrarticular, intrabronchial, intraabdominal, intracapsular,intracartilaginous, intracavitary, intracelial, intracerebellar,intracerebroventricular, intracolic, intracervical, intragastric,intrahepatic, intramyocardial, intraosteal, intrapelvic,intrapericardiac, intraperitoneal, intrapleural, intraprostatic,intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal,intrasynovial, intrathoracic, intrauterine, intravesical, intralesional,bolus, vaginal, rectal, buccal, sublingual, intranasal, or transdermalmeans. An anti-IL-23 antibody composition can be prepared for use forparenteral (subcutaneous, intramuscular or intravenous) or any otheradministration particularly in the form of liquid solutions orsuspensions; for use in vaginal or rectal administration particularly insemisolid forms, such as, but not limited to, creams and suppositories;for buccal, or sublingual administration, such as, but not limited to,in the form of tablets or capsules; or intranasally, such as, but notlimited to, the form of powders, nasal drops or aerosols or certainagents; or transdermally, such as not limited to a gel, ointment,lotion, suspension or patch delivery system with chemical enhancers suchas dimethyl sulfoxide to either modify the skin structure or to increasethe drug concentration in the transdermal patch (Junginger, et al. In“Drug Permeation Enhancement;” Hsieh, D. S., Eds., pp. 59-90 (MarcelDekker, Inc. New York 1994, entirely incorporated herein by reference),or with oxidizing agents that enable the application of formulationscontaining proteins and peptides onto the skin (WO 98/53847), orapplications of electric fields to create transient transport pathways,such as electroporation, or to increase the mobility of charged drugsthrough the skin, such as iontophoresis, or application of ultrasound,such as sonophoresis (U.S. Pat. Nos. 4,309,989 and 4,767,402) (the abovepublications and patents being entirely incorporated herein byreference).

Having generally described the invention, the same will be more readilyunderstood by reference to the following Examples, which are provided byway of illustration and are not intended as limiting. Further details ofthe invention are illustrated by the following non-limiting Examples.The disclosures of all citations in the specification are expresslyincorporated herein by reference.

EXAMPLES Materials and Methods

Patients

The trial enrolled patients aged ≥18 years with PsA for ≥6 months,fulfilling Classification Criteria for Psoriatic Arthritis (CASPAR);(Taylor W. et al. Arthritis Rheum 2006, 54: 2665-73) ≥3 tender and ≥3swollen joints, C-reactive protein [CRP]≥0.3 mg/dL, ≥3% body surfacearea (BSA) of plaque psoriasis; and inadequate response to standardtherapies (≥3 months of non-biologic disease modifying anti-rheumaticdrugs [DMARDs]; ≥4 weeks of oral corticosteroids or nonsteroidalanti-inflammatory drugs [NSAIDs]); or intolerance of such therapies)were eligible. Patients with one prior anti-TNFα agent were permitted,but limited to 20% of participants, following 8-12 weeks of washout.Patients were ineligible if they had a history or current signs ofsevere, progressive, or uncontrolled medical conditions or had currentor history of malignancy within 5 years, except nonmelanoma skin cancer(NMSC). Patients with history or symptoms of active tuberculosis (TB)were excluded. Patients could not participate if they had receivedguselkumab or adalimumab previously; other anti-TNF-α therapy within 3months; other treatment targeting IL-12/23, IL-17, or IL-23 within 6months; or any systemic immunosuppressants (e.g., methotrexate) orphototherapy within 4 weeks.

Study Design

The study was a double-blind, placebo-controlled study conducted at 34sites in seven countries (Canada, Germany, Poland, Romania, Russia,Spain, United States) from Mar. 27, 2015-Jan. 17, 2017. Patients wererandomized 2:1 (stratified by prior anti-TNFα use) to receivesubcutaneous guselkumab 100 mg or placebo at Week0, Week4, and every 8weeks (q8w). This dose regimen was selected based on the dose-responsein psoriasis, where a higher dose (200 mg q12w) did not yieldincremental benefit.

At Week16, all patients with <5% improvement in swollen and tender jointcounts were eligible for early-escape to open-label ustekinumab(placebo→ustekinumab, guselkumab→ustekinumab). Patients continuingplacebo crossed over to receive guselkumab 100 mg (placebo→guselkumab)at Week24, Week28, and q8w through Week44 with a final follow-up atWeek56. MTX (≤25 mg/week), oral corticosteroids (≤10 mg/day ofprednisone/equivalent), and NSAIDs were permitted but not required; withstable doses through Week24. Sulfasalazine (≤3 g/day) and leflunomide(≤20 mg/day) were permitted post-Week24. Other DMARDs and biologics wereprohibited through Week56.

This trial (NCT02319759) was conducted per Declaration of Helsinki andGood Clinical Practice guidelines. The protocol (available at NEJM.org)was approved by governing ethical bodies; patients provided writteninformed consent. Janssen Research & Development, LLC funded the studyand analyzed data (BD/YW/YZ/WB/XLX). All authors interpreted the dataand collaborated on manuscript preparation, supported by aJanssen-funded medical writer. All authors decided to submit themanuscript for publication and attest to data veracity/completeness andstudy fidelity to the protocol.

An institutional review board or ethics committee approved the studyprotocol at participating sites; patients provided written informedconsent before study initiation.

Assessments

Independent assessors evaluated joints for tenderness (N=68) andswelling (N=66, excluding hips). Patients reported pain (0-100 mm visualanalog scale [VAS]), global disease activity (0-100 mm VAS), andphysical function (Health Assessment Questionnaire-Disability Index[HAQ-DI]). Investigators completed the global assessment of diseaseactivity (0-100 mm VAS), and serum CRP was determined. The jointassessor also assessed dactylitis severity for each finger/toe on ascale of 0 (no dactylitis) to 3 (severe dactylitis), with a total scoreof 0-60, and the presence of enthesitis using the Leeds Enthesitis Index(LEI).

The Psoriasis Area and Severity Index (PAST) assessed skin diseaseseverity/extent. The 36-item Short-Form (SF-36) Health Survey assessedmental and physical health and quality of life. The primary endpoint wasthe proportion of patients meeting the ACR 20% improvement criteria(ACR20) at Week24. Secondary endpoints included ACR20 at Week16; andPASI75/90/100, ACR50/70, HAQ-DI, enthesitis/dactylitis improvements inpatients with baseline enthesitis/dactylitis, changes in SF-36 mentaland physical component summary (MCS and PCS) scores, and achievement ofminimal disease activity (MDA) criteria through Week56. Adverse events(AEs) were monitored.

Statistical Analyses

Efficacy analyses through Week24 employed the modified Intent-to-Treatpopulation (mITT or Full Analysis Set; randomized and treated patients).Treatment group comparisons employed the Cochran-Mantel-Haenszel teststratified by prior TNFα-inhibitor use for binary endpoints and a mixedmodel for repeated measures, analysis of variance, or Wilcoxon rank sumtest for continuous endpoints. To control type I error for multiplicity,two secondary analyses at Week24 (PASI75, HAQ-DI change) were to beperformed sequentially, contingent upon primary analysis/precedinghypothesis success (α=0.05; 2-sided). Further analytical details areprovided online.

Data handling rules were applied to all efficacy analyses throughWeek24. Patients who met treatment-failure criteria, early-escaped, orhad missing data were considered nonresponders for dichotomous ACR/MDAresponses after treatment-failure/early-escape through Week24. Forcontinuous endpoints through Week24, patients with missing baseline wereexcluded. Last-observation-carried-forward methodology was employed toimpute post-baseline missing data or data post-early-escape. ACR/MDAresponses through Week56 also were analyzed post-hoc in the mITTpopulation using nonresponder imputation (NRI) for treatment-failure,early-escape, or missing data.

Results Patients

Among 251 screened patients, 149 were randomized to placebo (N=49) orguselkumab (N=100). Seventeen (34.7%) placebo- and 10 (10.0%)guselkumab-treated patients qualified for early-escape to ustekinumab atWeek16. Three (6.1%) patients receiving placebo, 1 (3.4%) receivingplacebo→guselkumab, and 6 (6.0%) in the guselkumab group discontinuedstudy agent through Week44 (FIG. 1).

Baseline characteristics were generally similar between groups andindicated moderate-to-severe arthritis. Mean BSA/PASI scores appearedsomewhat higher with guselkumab vs. placebo, and more patients in theguselkumab vs. placebo groups had baseline dactylitis/enthesitis,although no difference was statistically significant. Most (87.9%)patients had previously received conventional DMARDs; 44.3% werereceiving MTX at baseline; and 8.7% previously received an anti-TNFαagent (Table 1).

Efficacy During Placebo-Controlled Period (Week 0-24)

The primary endpoint was met during the placebo-controlled period (Week0-24). 58.0% vs. 18.4% of guselkumab- vs. placebo-treated patients(P<0.001) achieved an ACR20 response at Week24. Sensitivity analyseswere confirmatory (Table 51), and results were consistent regardless ofconcomitant MTX use (Table 2). Significant improvement in ACR20 responsefor guselkumab vs. placebo was observed by Week4 (21.0% vs 0, p<0.001),reaching maximum by Week16 (60.0% vs. 16.3%; P<0.001; FIG. 2A). ACR50and ACR70 (FIG. 2B, 2C) responses were consistently higher amongguselkumab- than placebo-treated patients over time through Week24(ACR50: 34.0% vs. 10.2%, P=0.002; ACR70: 14.0% vs. 2.0%, P=0.023[calculated post hoc]) (Table 2). Significant improvements were observedin all ACR components at Week24 (P<0.001) (Table S2). Physical function,assessed by HAQ-DI, was significantly improved by guselkumab vs. placeboat Week24 (LSMean difference [95% CI] in HAQ-DI change from baseline:−0.31 [−0.47, −0.15]; P<0.001) (Table 2).

PASI75/90 responses were significantly higher for guselkumab vs. placeboby Week4 (data not shown) and through Week24 (PASI75: 78.6% vs. 12.5%,and PASI90: 66.3% vs. 6.3%, P<0.001; Table 2). PASI100 response wassignificantly higher at Week24 (39.8% vs. 6.3%; P<0.001).

Among those with baseline enthesitis, 56.6% vs. 29.0% of guselkumab- vs.placebo-treated patients had enthesitis resolution at Week24 (P=0.012).Similar findings were observed for dactylitis resolution at Week24(55.2% vs. 17.4%; P=0.001) (Table 2). Guselkumab yielded significantlygreater improvement in LEI/dactylitis scores than placebo (both withmedian percent improvements from baseline of 100.0% vs. 33.3%; P≤0.009)among patients with these baseline symptoms. Significantly higherproportions of guselkumab- than placebo-treated patients achieved MDAresponse at Week24 (23.0% vs. 2.0%; P=0.001; Table 2). Guselkumabsignificantly improved SF-36 PCS (mean change from baseline: 6.59 vs.0.46; P<0.001) and MCS (mean change from baseline: 4.95 vs. 0.42;P=0.002) scores vs. placebo by Week24 (Table 2).

Efficacy Post-Week24

Consistent with Week24 results, efficacy outcomes rapidly improvedfollowing crossover from placebo→guselkumab at Week24 and weremaintained through Week44 (last on-treatment efficacy assessment) andWeek56 (final follow-up visit) among patients who continued guselkumab.ACR/MDA responses through Week56 are shown using NRI, FIGS. 2A-D) orbased on observed data (Table S3).

Safety

Guselkumab was generally well tolerated. Through Week24, 36.0% ofguselkumab- and 32.7% of placebo-treated patients reported ≥1 AEs.Through Week56, 39.5% of guselkumab-treated patients, including 46% ofthose receiving guselkumab from Week0→Week44, reported ≥1 AEs. AEincidences were comparable regardless of concomitant MTX use and showedno disproportional increase with longer guselkumab exposure (Table 3).

No deaths, anaphylactic/serum sickness-like reactions, or suicidalideation were reported through Week56. Serious AEs were reported by oneplacebo (2.0%, joint injury) and one guselkumab (1.0%, myocardialinfarction) patients through Week24 and by five additionalguselkumab-treated patients (osteoarthritis, pneumonia, pupils unequal,radius fracture, ulcerative keratitis) through Week56. All serious AEswere considered unrelated to study drug by investigators and resolved.The patient with myocardial infarction presented with multiple riskfactors (male >45 years, hypertension, hyperlipidemia, family history ofearly coronary artery disease [<55 years], obesity, tobacco usehistory), and had atherosclerosis at baseline with prior carotidendarterectomy. Two (1.6%) guselkumab-treated patients discontinuedtreatment due to AEs through Week44 (last study agent administration)(Table 3). Except one case of basal cell carcinoma in aguselkumab-treated woman (67-year-old Caucasian/fair skin, frequentlyoutdoors), no other malignancy occurred. No injection-site reactionswere reported among 750 guselkumab administrations.

Investigators-identified infections occurred in 16.0% and 24.0% ofguselkumab- and placebo-treated patients, respectively, through Week24,and in 20.9% of all guselkumab-treated patients through Week56. Seriousinfections occurred in one (0.8%) guselkumab-treated 78-year-old womanwho had two episodes of acute pneumonia (Days179/209) and subsequentlydiscontinued treatment. No candidiasis, active tuberculosis, oropportunistic infections were reported.

Five (3.9%) guselkumab-treated patients reported AEs ofneutropenia/neutrophil count decreased, of which four also reportedleukopenia/WBC decreased. However, Grade-2 (1000-1500 cells/mm³) orGrade-3 (500-1000 cells/mm³) neutropenia per National Cancer InstituteCommon Terminology Criteria for AEs (NCI-CTCAE) occurred in three (3.0%,two receiving MTX) and one (1.0%, no MTX), respectively,guselkumab-treated patients through Week56. The patient with Grade-3neutropenia discontinued treatment, with subsequent spontaneousresolution. Grade-2 neutrophil count decreases were observed for justone visit among each of the three patients and resolved spontaneouslywith continuous guselkumab. No infections were reported in these fourpatients through the final follow-up. The proportions of patients withalanine aminotransferase (ALT) or aspartate aminotransferase (AST)increase meeting NCI-CTCAE Grade 1 (1.0-3.0× upper limit of normal[ULN]) or higher criteria were generally comparable between placebo andguselkumab through Week24. Through Week56, four (3.1%)guselkumab-treated patients (three with concomitant MTX) demonstratedALT increases and five (3.9%) (four with MTX including one with chronicliver disease at baseline) had AST increases meeting NCI-CTCAE Grade 2(3.0-5.0×ULN). Grade 3 (5.0-20.0×ULN) or higher ALT/AST increasesthrough Week56, not observed in guselkumab-treated patients, occurred inone (2.0%) placebo-treated patient.

Through Week56, 4.7% of guselkumab-treated patients developednon-neutralizing antibodies to guselkumab. No unexpected safety findingswere observed in patients early-escaping to ustekinumab through Week56(Table 3).

Discussion

Guselkumab, a human monoclonal anti-IL-23p19 antibody recently approvedin the United States for treating moderate-to-severe psoriasis (JanssenBiotech, Inc, TREMFYA® https://www.tremfyahcp.com), is thefirst-in-class to demonstrate efficacy in PsA. In this POC trial,guselkumab 100 mg at Week0, Week4, and q8w significantly reduced jointand skin disease, enthesitis/dactylitis, and improved physicalfunction/quality of life. This study met its primary and all secondaryendpoints. Significant improvement of joint/skin disease was observed atWeek4 (first post-baseline assessment); improvement was consistentlyobserved in all ACR components and in patient subgroups defined bydemographic/disease characteristics (data not shown) andprior/concomitant medications (Table 2). Efficacy was well maintainedthrough ˜1 year. The robust efficacy demonstrated by guselkumab verifieda critical role of IL-23 in PsA pathogenesis, consistent with findingsfrom previous PsA ustekinumab studies. Both guselkumab and ustekinumabhave demonstrated very high clinical response rates in clinical studiesof moderate-to-severe psoriasis (Leonardi C L et al. Lancet 2008,371:1665-74; Papp K A et al, Lancet 2008, 371:1675-84; Blauvelt A. etal, 2017, 76:405-417; Reich K et al, J Am Acad Dermatol 2017, 76:418-31,also highlighting the central role of IL-23 in both psoriasis and PsA.

Genetic polymorphisms in IL-23/IL-23R genes are linked to susceptibilityin psoriasis, PsA, and IBD (Bowes J et al, Ann Rheum Dis 2011,70:1641-44; Duerr R H et al, Science 2006, 314:1461-3; Liu Y et al. PLoSGenet 2008, 4(3):e1000041; Nair R P et al. Nat Genet 2009, 41:199-204.PsA patients have increased risk for IBD (Orchard T R et al, Gut 1998,42:387-91 and often demonstrate gut bacterial profiles like IBD patients(Scher J U et al, Arthritis Rheum 2015, 67:128-39. Thus, the commonimmune-mediated inflammatory pathways of the “skin-joint-gut axis” inPsA may be microbiome-induced/mediated, and IL-23 may be crucial to thismechanism. Ustekinumab effectively treats Crohn's disease (CD) (Feagan BG et al, N Engl J Med 2016, 375:1946-60, and two agents targetingIL-23p19 (risankizumab/MEDI2070) have shown promising results in phase-2CD studies Sands B E et al, J. gastro. 2017, S0016-5085(17)35401-X;Feagan B G et al, Lancet 2017, 389:1699-709. Conversely, two anti-IL-17agents (secukinumab/brodalumab) did not improve or worsened CD inphase-2 trials (Targan S R et al, Am J Gastroenterol 2016, 111:1599-607,Hueber W et al. Gut 2012, 61:1693-700, and new onset/worsened IBD wasreported in phase-3 secukinumab and ixekizumab studies (Baeten D et al.N Engl J Med 2015, 373:2534-48; Gordon K B et al, N Engl J Med 2016,375:345-56. Herein, no patient had baseline IBD and no AE of IBD wasreported. Guselkumab efficacy in IBD requires evaluation in futureclinical studies.

In our PsA population, guselkumab safety through Week56 was generallyconsistent with that observed in psoriasis (Blauvelt A. et al, 2017,76:405-417; Reich K et al, J Am Acad Dermatol 2017, 76:418-31), withfrequencies of AEs, including infections, comparable to placebo throughWeek24. NCI-CTCAE Grade-2/3 neutrophil decreases occurred in four (4.0%)guselkumab-treated patients through Week56 and were not associated withMTX use. Neutrophil homeostasis/tissue trafficking are regulated by anIL-17/granulocyte-colony-stimulating-factor-cytokine-controlled loop(Krstic A et al, Immunol Res 2012; 52:34-41, with IL-17 playing animportant role in granulopoiesis (Rahman P et al, Arthritis Rheum 2008;58:1020-5; Langley R G et al, N Engl J Med 2014; 371:326-38; NovartisPharmaceuticals Corporation. COSENTYX®,https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/cosentyx.pdf).Increased incidence of Grade-1/2/3 neutropenia was reported in largephase-3 trials of the anti-IL-17 antibodies secukinumab (Langley R G etal, N Engl J Med 2014; 371:326-38; Novartis Pharmaceuticals Corporation.COSENTYX®,https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/cosentyx.pdf),ixekizumab (Eli Lilly and Company,http://pi.lilly.com/us/taltz-uspi.pdf) and brodalumab (Lebwohl et al, NEngl J Med 2015; 373:1318-28); however, in the combined analysis of twolarge, phase-3, guselkumab psoriasis trials (Blauvelt A. et al, 2017,76:405-417; Reich K et al, J Am Acad Dermatol 2017, 76:418-31), no casesof Grade-3 or Grade-4 neutropenia were observed and the frequencies ofGrade-2 neutropenia were comparable for placebo (3/416, 0.7%) andguselkumab 100 mg (6/821, 0.7%) treatment through Week16 during theplacebo-controlled period. Through Week48, Grade-4 neutropenia was notobserved, and Grade-3 neutropenia occurred in 1/1,363 (0.1%) guselkumab-and 2/576 (0.3%) adalimumab-treated patients. The frequencies of Grade-2neutropenia were similar between guselkumab- (22/1363, 1.6%) andadalimumab- (16/576, 2.8%) treated patients. Guselkumab had noremarkable effect on other laboratory parameters, including livertransaminases, glucose, or lipids. Guselkumab's effect on neutrophilcounts, liver enzymes, and other laboratory parameters among PsApatients will be further evaluated in large phase-3 trials.

Study limitations include small sample size, relatively short duration,and no assessment of dose response. Lack of an active comparator alsolimits comparison with other PsA therapies. ACR20 response was selectedas the appropriate primary endpoint for this phase-2 POC study withlimited sample size, and ACR50, which may be more clinically meaningful,was evaluated as a secondary endpoint, with both showing significantimprovement with guselkumab treatment. Guselkumab efficacy/safety in PsApatients with no or limited psoriasis require further evaluation, sinceall study participants had ≥3% BSA of psoriasis. Too few patients werepreviously exposed to TNFα-inhibitors to reliably estimate clinicalresponse in this population, as were the numbers of patients withspecific PsA subsets (e.g., psoriatic spondylitis). Small imbalances inbaseline BSA, PASI, enthesitis, dactylitis and MTX use were due to thesmall number of placebo patients and are not expected to impactinterpretation of efficacy findings.

Thus, among patients with active PsA and ≥3% BSA of psoriasis,guselkumab significantly improved joint symptoms, physical function,psoriasis, enthesitis, dactylitis, and quality of life, with a favorablesafety profile possibly differing from IL-17-inhibitors. Findingsconfirm the critical role of IL-23, and validate it as a treatmenttarget, in PsA.

Additional Clinical Indices Routine Assessment of Patient Index Data(RAPID3)

The Routine Assessment of Patient Index Data 3 (RAPID3) was also used toevaluate the effect of guselkumab (GUS) on patients with psoriaticarthritis (PsA). RAPID3 (0-30) is derived from the Multi-DimensionalHealth Assessment Questionnaire (MDHAQ) numerical rating scale (0-10)for pain and general health. A change of 5.1 in RAPID3 score wasidentified as the minimally important difference (MID) in PsA, andRAPID3≤3.0 was used to define PsA remission.

In a phase 2 trial, patients with active PsA and ≥3% body surface areaof plaque psoriasis despite current or previous treatment withstandard-of-care therapies, including anti-TNFα agents, were randomized2:1 to receive GUS 100 mg (n=100) or placebo (PBO, n=49) subcutaneouslyat weeks 0, 4, and every 8 weeks (q8w) thereafter through week44. Atweek16, patients from either group with <5% improvement from baseline inboth swollen and tender joint counts were eligible for early escape toopen-label ustekinumab. At week24, all remaining PBO patientscrossed-over to receive GUS 100 mg, and then received GUS at week28 andq8w thereafter through week44. Change in RAPID3 and proportion ofpatients achieving MID were compared between treatments. Correlations ofRAPID3 scores with the PsA Disease Activity Score (PASDAS), GRACE index,Disease Activity in Psoriatic Arthritis (DAPSA), and Modified CompositePsoriatic Disease Activity Index (mCPDAI) were evaluated using Spearmancorrelation.

The mean (SD) RAPID3 score at baseline was 16.9 (5.19). At Week 24,patients in the GUS group achieved statistically significantly greaterimprovement in RAPID3 (5.81+/−6.0) than the PBO group (0.57+/−0.51,p<0.001), and 50% patients in the GUS group versus 20.4% in the PBOgroup achieved an MID (p<0.001). Higher remission rate in the GUS thanthe PBO group (14.0% versus 2.4%, p=0.022) was observed. At week44, mean(SD) improvement was further increased from week24 (6.36 [6.205] to 7.48[6.310]) in patients who continued Guselkumab. Among patients whoswitched from PBO to GUS at week24, mean (SD) improvement in RAPID3 wasincreased from 2.28 (5.244) at week24 while on placebo to 7.60 (6.588)at week44 after switching to GUS. The RAPID3 score was highly correlatedwith PASDAS (r=0.84, p<0.001), GRACE index (r=0.89, p<0.001), DAPSA(r=0.77 p<0.001) and mCPDAI (r=0.65, p<0.001) at week16.

Lead Enthesitis Index (LEI)

Enthesitis was assessed using the Leeds enthesitis index (LEI).Enthesitis scores during the 24-week double-blind treatment wereanalyzed using LOCF imputation for missing data and early escape.Enthesitis after week24 was analyzed using observed data.

Of 149 total patients with active PsA, 107 (72%) presented withenthesitis at baseline (PBO N=31, mean [SD] LEI=2.6 [1.48], median[range]=2.0 [1, 6]; GUS N=76, mean (SD) LEI=2.7 [1.54], median[range]=2.0 [1, 6]) and 85 continued at Week 24 (PBO→GUS N=18; GUS→GUSN=67). Except for higher tender/swollen joint counts & CRP, baselinecharacteristics of the enthesitis subset was similar to the overallpopulation. Guselkumab significantly reduced the LEI by Week 8 (mean[SD]] change from baseline, PBO: −0.4 [1.59]; GUS: −1.2 [1.65];p=0.037), and through Week 24 (mean [SD] change from baseline, PBO: −0.7[1.53]; GUS: −1.5 [1.81]; p=0.045). After Week 24, the PBO→GUS groupachieved rapid, sustained resolution (Week 56: mean[SD] change fromBL=−2.1 [1.65]; 62.5% of patients with resolution), similar to GUS→GUSgroup (Week 56: mean[SD] change from BL=−1.9 [1.59], 70.8% of patientswith resolution). Guselkumab also significantly increased the percent ofpatients with enthesitis resolution. Improvement in enthesitis wasobserved at each enthesitis site assessed. Improvement was greater inACR20 responders versus non-responders in Guselkumab-treated patients.Enthesitis improvement was correlated with reduction in tender (R=0.37,p=0.001), swollen (R=0.27, p=0.020) joint counts, physician's (R=0.47,p<0.0001) and patient's global assessment of disease activity (R=0.32,p=0.005), change in SF36 PCS (R=0.27, p=0.02) and MCS (R=0.35, p=0.002).

Guselkumab treatment produces rapid and sustained improvement ofenthesitis in patients with active PsA, which correlates withimprovement in joint symptoms and patient-reported outcomes.

Dactylitis Index

Dactylitis was assessed by scoring each digit from 0-3 (0=absent,1=mild, 2=moderate, 3=severe), for a combined score of 0-60. Sensitivityanalysis of change from BL through week24 in dactylitic digits wasperformed (combined score 20). Dactylitis scores during the 24-weekdouble-blind treatment was analyzed using LOCF imputation for missingdata and early escape (EE). Dactylitis after week24 was evaluated usingobserved data.

Of 149 patients, 81 presented with dactylitis at baseline (PBO N=23,mean[SD]=3.9[3.01]; GUS N=58, mean[SD]=6.5[6.15]) and 66 continued tothe active treatment period (PBO→GUS N=16; GUS→GUS N=50). The dactylitissubset was similar to the overall population at baseline characteristicsexcept for higher median values for the number of swollen joints, thenumber of tender joints, and CRP. At weeks 16 and 24, the GUS group hada significantly greater reduction in the dactylitis score (week24 mean[SD] change from baseline, PBO: −0.4 [6.06]; GUS: −3.8 [4.93]; p=0.006)and a greater % of patients w/ dactylitis resolution, compared to thePBO group (FIGS. 7A and 7B). Consistent results were obtained withnumber digits with dactylitis (week24 mean [SD] change from baseline,PBO: −0.2 [3.04]; GUS: −2.1 [2.21]; p=0.003). Improvement in dactylitisseen at week24 was maintained in the GUS→GUS group (week56: mean[SD]change from BL=−5.5 [4.84], 75% of pts w/resolution) and the values forthe PBO→GUS group (week56: mean[SD] change from BL=−4.4 [3.50], 93.7% ofpatients with resolution) approached those of the GUS→GUS group.Improvement in dactylitis was greater in ACR20/ACR50 responders versusnon-responders in GUS-treated patients (Table S5) and was significantlycorrelated with improvement in TJC (R=0.38, p=0.004), SJC (R=0.50,p<0.0001), & HAQ-DI score (R=0.33, p=0.013).

GUS is efficacious in resolving symptoms of dactylitis in patients withactive PsA. This effect on dactylitis is correlated with improvement injoint symptoms and physical function.

Composite Endpoints PASDAS, GRACE, mCPDAI and DAPSA

Psoriatic ArthritiS Disease Activity Score (PASDAS), GRAppa CompositescorE (GRACE) Index, modified Composite Psoriatic Disease Activity Index(mCPDAI), and Disease Activity Index for PSoriatic Arthritis (DAPSA) arecomposite indices recently developed to assess disease activity inpsoriatic arthritis (PsA). Given the diverse and highly individualclinical and radiographic presentations of psoriatic arthritis (PsA),composite indices may be more useful in assessing disease activity anddefining clinically meaningful treatment targets compared withconventional scoring systems. While multiple PsA composite indices haverecently been proposed, there currently is no consensus within therheumatology community regarding the choice of composite diseaseactivity measures, and performance data for PsA-specific compositeindices are lacking. The effect of guselkumab (GUS) on these indices wasevaluated in a Phase 2 study in patients with active PsA. Theperformance of the PsA composite indices was assessed using standardizedmean difference, effect size and standardized response mean.

Materials and Methods Ethics

This study (NCT02319759) was conducted according to Declaration ofHelsinki and Good Clinical Practice guidelines. The protocol wasapproved by each site's governing ethical body; patients providedwritten informed consent.

Study Design

As reported (Deodhar2018), patients enrolled into this double-blind,placebo-controlled, parallel-group, two-arm, multicenter trial werecentrally randomized (2:1) to receive subcutaneous guselkumab orplacebo. Study drugs were provided in identical prefilled syringes; allpatients received the same number of injections at the same time points.

Patients randomized to guselkumab received guselkumab 100 mg at Weeks0,4, 12, 20, 28, 36, and 44, and placebo at Week24. Patients randomized toplacebo received placebo at Weeks0, 4, 12, and 20 and guselkumab 100 mgat Weeks24, 28, 36, and 44.

Patients with <5% improvement in swollen and tender joint counts (TJCsand SJCs) at Week16 early escaped to open-label ustekinumab (JanssenBiotech, Inc., Horsham, Pa., USA), i.e., placebo→ustekinumab orguselkumab→ustekinumab, at Weeks16, 20, 32, and 44 according to approvedcountry-specific prescribing information. A final follow-up visitoccurred at Week56.

Patients

Eligible patients included adults with PsA for ≥6 months, fulfillingClassification Criteria for Psoriatic Arthritis (CASPAR) (Taylor2006),≥3 tender and ≥3 swollen joints, C-reactive protein (CRP) ≥0.3 mg/dL,≥3% BSA of plaque psoriasis, and an inadequate response to standardtherapies (Deodhar2018). Patients who received one prior anti-tumornecrosis factor alpha agent were permitted, but limited to 20% ofparticipants, following 8-12 weeks of washout. Stable doses ofmethotrexate (MTX; ≤25 mg/week), oral corticosteroids (≤10 mg/day ofprednisone/equivalent), and nonsteroidal anti-inflammatory drugs werepermitted, but not required, through Week24. Sulfasalazine (≤3 g/day)and leflunomide (≤20 mg/day) were permitted following Week24. Otherdisease-modifying antirheumatic drugs (DMARDs) and biologics wereprohibited.

Procedures

Independent assessors evaluated joint tenderness (N=68) and swelling(N=66, excluding hips). Patients reported pain (0-100 mm visual analogscale [VAS]), global disease activity (0-100 mm VAS for arthritis,psoriasis, and both), and physical function (HAQ-DI). Investigatorscompleted the global assessment of disease activity (0-100 mm VAS), andserum CRP was determined. The joint assessor also evaluated dactylitis(0-none to 3-severe) for each finger and toe (total score 0-60) andenthesitis using the LEI. The PASI assessed skin disease severity andextent. The SF-36 assessed physical and mental HRQoL. Key efficacyassessments were performed at screening, baseline, every 4 weeks throughWeek36, Week44, and Week56.

Outcomes

As reported (Deodhar A et al. Lancet, 2018, 391:2213-24), patientsachieved MDA if meeting ≥5/7 criteria: TJC≤1/68, SJC≤1/66, PASI≤1,patient pain VAS≤15, patient global disease activity VAS (arthritis andpsoriasis)≤20, HAQ-DI≤0.5, and tender entheseal points ≤1 (Coates2010).Patients meeting all seven criteria achieved VLDA (Coates L C et al, AnnRheum Dis 2010; 69:48-53).

The PASDAS (Helliwel12013, Helliwel12014b) was calculated using: patientglobal VAS (arthritis and psoriasis, 0-100 mm), physician global VAS(0-100 mm), TJC, SJC, CRP (rescaled to mg/L), enthesitis (LEI),dactylitis (scores of 0-3 recoded to 0-1, where any score >0 equaled 1),and the PCS score of the SF-36. Disease activity cutoffs were: very low(≤1.9), low (>1.9-≤3.2), moderate (>3.2-<5.4), high (≥5.4) (Helliwell PS et al, Ann Rheum Dis 2010, 69:48-53).

The GRACE derives from the Arithmetic Mean of the Desirability Function(AMDF), calculated by transforming the following variables, usingpredefined algorithms and expressing the total score as a mean rangingfrom 0-1, where 1 indicates a better state than 0: TJC, SJC, HAQ-DI,patient's global VAS (arthritis and psoriasis, 0-100 mm), patient'sassessment of skin disease activity VAS (0-100 mm), patient's globalassessment VAS (arthritis, 0-100 mm), PASI, derived PsAQoL index(PsAQoL=25.355+[2.367×HAQ-DI]−[0.234×SF-36 PCS score]−[0.244×SF-36mental component summary score]). The GRACE was then calculated as(1−AMDF)×10, with the following disease activity cutoffs: low (≤2.3),moderate (>2.3-<4.7), high (≥4.7) (Helliwell P S et al, Ann Rheum Dis2010, 69:48-53; Helliwell P S et al, Arthritis Care Res2014b;66:749-56).

The CPDAI (Mumtaz2011), modified for PsA (mCPDAI) to assess four domains(joints, skin, entheses, dactylitis), was calculated based on TJCs,SJCs, HAQ-DI, PASI, and dactylitis/enthesitis scores. Within eachdomain, scores of 0-3 were assigned according to predefined cutoffs andsummed to yield a total score of 0-12. Adjusted disease activity cutoffs([CPDAI/15]×12) were: low (≤3.2), moderate (>3.2-<6.4), high (≥6.4)(Helliwell P S et al, Arthritis Care Res 2014b;66:749-56).

The DAPSA was calculated as the sum of the TJC, SJC, CRP (mg/dL),patient assessment of pain VAS (0-10), and patient global assessment VAS(arthritis, 0-10) (Helliwel12014b). The disease activity cutoffs were:remission (≤4), low (>4-≤14), moderate (>14-≤28), high (>28) (Schoels MM et al, Ann Rheum Dis 2016; 75:811-8).

Statistical Analyses

All efficacy analyses through Week24 included patients who received ≥1administration of randomized study drug with data handling rules applied(full analysis set). Patients who met treatment-failure criteria (i.e.,discontinued study agent resulting from lack of efficacy/PsA worsening,initiated or increased the dose of MTX or oral corticosteroids for PsA,or initiated protocol-prohibited medications and/or therapies) wereconsidered nonresponders for MDA/VLDA after treatment failure throughWeek24, as were patients who had missing data or early escaped atWeek16. For continuous endpoints and response endpoints derived fromcontinuous variables through Week24, patients with missing baseline datawere excluded. Last-observation-carried-forward methodology was employedto impute post-baseline missing data or data post-early escape.Post-Week24, all patients received active treatment, and no statisticalcomparisons were planned. Therefore, observed data were employed tosummarize post-Week24 data among the 29 patients who early escaped fromplacebo→guselkumab and the 86 guselkumab-randomized patients who did notearly escape at Week16 and did not discontinue study drug prior toWeek24, with Week24 data in these patients included as a reference.Statistical analyses were performed using SAS version 9.2 (SASInstitute, Inc., Cary, N.C., USA).

To examine correlations between improvements in disease activitydetected by each PsA composite index with improvements in HRQoL, meanimprovements from baseline to Week24 in the SF-36 PCS score weresummarized by disease activity state among guselkumab-treated patients.Changes in composite index scores from baseline to Week16 and Week24were summarized using descriptive statistics, and between-treatmentcomparisons of change in composite indices were performed using ananalysis of variance (ANOVA). Between-treatment comparisons of theproportions of patients achieving very low disease activity orremissionwere performed post hoc with Fisher's Exact test.

The relative performance of each index was assessed via calculation oftreatment group effect size (ES; the absolute value of the meandifference between baseline and Week24 values divided by the standarddeviation [SD] at baseline). ES values are used to categorize treatmenteffects as trivial (<0.20), small (≥0.20 to <0.50), moderate (≥50 to<0.80), or large (≥0.80) (Altman1991). Additional comparative statisticsincluded standardized mean differences (SMDs; the absolute value of meandifference in change from baseline [guselkumab minus placebo] divided bythe pooled SD of change from baseline at Week24) and treatment groupstandardized response means (SRMs; the absolute value of mean changefrom baseline divided by the SD of change from baseline at Week24). Theproportions of patients meeting residual disease activity criteria(defined by CRP≤upper limit of normal [0.287 mg/dL], dactylitis score=0,enthesitis LEI score=0, PASI≤1, TJC≤1/68, SJC≤1/66) were assessed amongpatients achieving PsA-specific composite endpoint low diseaseactivity/remission states, MDA, or VLDA at Week24.

Results Disposition and Baseline Characteristics

This Phase 2 trial was conducted at 34 sites (Canada, Germany, Poland,Romania, Russia, Spain, United States). Patient screening began on Mar.27, 2015, and the last patient visit was completed on Jan. 17, 2017.Patient disposition has been reported (Deodhar2018). Briefly, 149patients were randomized to placebo (N=49) or guselkumab 100 mg (N=100).Seventeen of 49 (34.7%) placebo- and 10/100 (10.0%) guselkumab-treatedpatients qualified for early escape to ustekinumab at Week16.Twenty-nine of 49 (59.2%) patients in the placebo group crossed over toreceive guselkumab at Week24; 28 placebo→guselkumab patients completedthe study through Week44. Eighty-six of 100 (86.0%) patients in theguselkumab group completed Week24 and continued guselkumab treatment; 84patients completed the study through Week44.

Baseline characteristics were generally similar between randomizedgroups and indicated moderate-to-severe arthritis, with substantialdisability (mean HAQ-DI: 1.39). At study outset, 71.8% and 54.4% ofpatients presented with enthesitis and dactylitis, respectively(Deodhar2018). Baseline mean PASDAS (6.5), GRACE (6.1), mCPDAI (7.5),and DAPSA (46.7) scores also demonstrated moderate-to-high diseaseactivity across treatment groups. Further, the proportions of patentswith moderate-to-high disease activity at baseline were comparablebetween treatment arms for each of the PASDAS (both 100%), GRACE (both100%), mCPDAI (both ˜96%), and DAPSA (100% and 99%) composite indices(FIGS. 3C-J).

Validation of PsA-Specific Composite Indices Using SF-36 PCS as anAnchor

Changes from baseline to Week24 in SF-36 PCS scores were consistent withdisease activity states defined by each PsA composite index inguselkumab-treated patients. Specifically, the largest improvements inSF-36 PCS were observed in patients with remitted/very low/low diseaseactivity at Week24 (9.5-12.9 across indices), which were significantlyhigher than those observed in patients with moderate (4.1-6.4; p<0.05)or high (0.6-2.7; p<0.001) disease activity at Week24 (FIGS. 4A-D).

The Effect of Guselkumab on PsA-Specific Composite Endpoints

Placebo-Controlled Period:

Guselkumab significantly improved disease activity from baseline toWeek24, relative to placebo, when assessed using the PASDAS (meanchanges: −2.5 vs. −0.5, respectively), GRACE (−2.7 vs. −0.4), mCPDAI(−3.9 vs. −0.8), and DAPSA (−23.1 vs.-5.0) composite indices (allp<0.001; FIGS. 3D, 3F, 311, 3J). Consistently, significantly higherproportions of guselkumab- than placebo-treated patients achieved lowdisease activity when assessed by the PASDAS (35.0% vs. 4.1%; p<0.001),GRACE (29.6% vs. 2.1%; p<0.001), mCPDAI (51.0% vs. 16.7%; p<0.001), andDAPSA (40.0% vs. 12.2%; p<0.01) composite indices.

Further, more patients achieved very low disease activity based onPASDAS (8.0% vs. 0, p=0.053) and significantly more patients achievedDAPSA remission (12.0% vs. 0; p<0.01) (FIGS. 3C, 3E, 3G, 3I). Forcomparison, as reported previously (Deodhar2018), 23% ofguselkumab-treated patients achieved MDA vs. 2.0% of placebo-treatedpatients (p=0.001) (FIG. 3A). A similar response pattern was observedfor VLDA, i.e., 6% of guselkumab-treated patients vs. no placebo-treatedpatients (p=0.076) (FIG. 3B).

Active-Treatment Period:

In the post-Week 24 efficacy analysis population, observed mean changesin the PsA composite disease activity index scores at Week44 are shownin FIGS. 5D, 5F, 5H, 5J; Week24 data in the same population are includedfor reference. The improvements afforded by guselkumab at Week24 weresustained through Week44 in guselkumab-randomized patients, and similarimprovements were realized in placebo-randomized patients who receivedguselkumab from Week24 through Week44. Also among patents who crossedover from placebo→guselkumab at Week24, the proportions of patients withlow disease activity were higher at Week44 than Week24 prior toguselkumab receipt (i.e., PASDAS very low+low: 39.3% at Week44 vs. 7.1%at Week24; GRACE: 39.3% vs. 7.1%%, respectively; mCPDAI: 75.0% vs.25.0%, respectively; and DAPSA remission+low: 50.0% vs. 20.7%,respectively) and were generally consistent with those observed atWeek44 among patients receiving guselkumab from Week0 forward (i.e.,PASDAS: 28.6% and 30.1%, respectively; GRACE: 39.3% and 42.2%,respectively; mCPDAI: 75.0% and 63.9%, respectively; and DAPSA: 35.7%and 32.1%, respectively; FIGS. 5C, 5E, 5G, 5I). In guselkumab-randomizedpatients, PASDAS and DAPSA low disease activity response rates weremaintained from Week24→Week44 (last on-treatment efficacy assessment,i.e., 29.1%→30.1% for PASDAS and 31.4%→32.1% for DAPSA), while PASDASvery low disease activity (9.3%→15.7%), DAPSA remission (12.8%→19.0%)(FIGS. 5C, 5I), MDA (26.7%→34.5%) and VLDA (7.0%→13.1%) (FIGS. 5A, 5B)response rates all increased from Week24→Week44.

Performance of PsA-Specific Composite Endpoints in Detecting TreatmentEffects at Week24

The SMD (5.16-8.13), ES (1.12-2.29), and SRM (1.14-1.58) statisticsindicated that guselkumab elicited a large effect in treating thediverse manifestations of PsA compared with placebo, regardless ofcomposite index employed (FIGS. 6A-C). Based on SMD, the PASDAS (8.14)and GRACE (8.84) indices appeared to be more sensitive than mCPDAI(7.21) and DAPSA (5.16) in distinguishing guselkumab treatment effectsrelative to placebo (FIG. 6A). The ES and SRM statistics also indicatedthat PASDAS (2.29 and 1.58, respectively) and GRACE Index (2.18 and1.55, respectively) were more sensitive than mCPDAI (1.72 and 1.40,respectively) and DAPSA (1.12 and 1.14, respectively).in detectingguselkumab treatment effects (FIG. 6B, 6C).

Evaluation of Residual Disease Activity Among Guselkumab-TreatedPatients Who Achieved Low/Very Low Disease Activity, Remission, MDA, orVLDA at Week24 Based on PsA Composite Indices

The residual skin disease criterion (PASI≤1) was met in ≥80% of patientsachieving PASDAS/GRACE/mCPDAI low or very low disease activity and/orMDA/VLDA; 75.0% of patients achieving DAPSA remission and 70.4% ofpatients achieving DAPSA low disease activity also demonstrated PASI≤1.The residual TJC criterion (≤1) was met in 100% of patients achievingPASDAS very low disease activity, DAPSA remission, and/or VLDA; in 87.5%of patients achieving MDA; and in 74.1-79.3% of patients achieving lowdisease activity based on PASDAS, GRACE, mCPDAI, and DAPSA. The residualSJC criterion (≤1) was met in 100% of patients achieving VLDA; in only˜60% in patients achieving PASDAS very low disease activity, DAPSAremission, and/or MDA; and in only ˜30-40% of patients achieving lowdisease activity based on PASDAS, GRACE, mCPDAI, and DAPSA. The majorityof patients achieving low or very low disease activity or remissionaccording to the PsA-specific indices or MDA/VLDA had no enthesitis ordactylitis, but >50% had elevated CRP (>0.287 mg/dL). All patients whoachieved PASDAS very low disease activity and −91% of those who achievedDAPSA remission also met MDA criteria, while <40% also met VLDA criteria(Table S4).

Discussion

Guselkumab has demonstrated efficacy in a Phase 2 trial of patients withactive PsA and ≥3% BSA affected by psoriasis (Deodhar A et al, Lancet.2018, 391:2213-24). In this report of the same trial, guselkumabtreatment effects were assessed using composite indices. Guselkumabsignificantly decreased PASDAS/GRACE/mCPDAI/DAPSA scores vs. placebo,and significantly more guselkumab-than placebo-treated patients achievedMDA and low disease activity states. Overall, PASDAS/GRACE were moresensitive than mCPDAI/DAPSA at detecting treatment effect.

The MDA and VLDA assess joint, skin, and entheseal disease inconjunction with physical function; both be used as response criteria(defining low and very low disease activity, respectively) and providetreatment targets. The PASDAS and GRACE were developed usinglongitudinal observational data derived from a large internationalcohort of PsA patients (Helliwell 2013). The PASDAS more heavily weightsthe patient and physician global assessments than it does joint, skin,dactylitis, enthesitis, acute-phase response, and HRQoL domains, whilethe GRACE places equal emphasis on each of its domains (joints, skin,function, QoL, global assessments). The domain-based mCPDAI, whichassesses axial and peripheral joints, skin, entheses, and dactylitis,employs predefined cutoffs to categorize disease severity that werederived from published literature and expert consensus, while the DAPSAwas developed from a clinical cohort of PsA patients to assess jointdisease, acute-phase response, and patient assessments of pain andoverall disease activity. In this study, the aforementioned PsA-specificindices were validated using the SF-36 PCS score as an anchor, which maybe partly circular given that it is a component of the PASDAS. Resultsshowed that the largest improvements in SF-36 PCS scores occurred inpatients with remitted/very low/low disease activity according to eachindex at Week24, and these improvements were significantly higher thanthose observed in patients with moderate or high disease activity atWeek24. Of note, the PASDAS, GRACE and DAPSA composite measures alsowere externally validated in PsA using radiographic data from thegolimumab GO-REVEAL PsA trial. In that analysis, each index was able todifferentiate the progression of structural damage of peripheral jointsin relation to disease outcome (Helliwell P S et al, Arthritis Care Res2018, 70:797-800).

As reported herein, additional efficacy assessments in the guselkumabPhase 2 PsA study demonstrated that guselkumab significantly decreaseddisease activity from Week0→Week24 relative to placebo based on the MDA,VLDA, PASDAS, GRACE, mCPDAI, and DAPSA. Additionally, significantly moreguselkumab- than placebo-treated patients achieved a state of lowdisease activity according to each of the PsA-specific compositeindices. Improvements in disease activity were maintained through Week44in guselkumab-randomized patients and were observed from Week24→Week44in placebo→guselkumab patients. Findings were consistent with thetrial's primary efficacy endpoint (i.e., Week24 ACR20 response: 58% vs.18%; p<0.0001) (Deodhar2018), as well as for the general compositemeasures of disease activity evaluated in this trial (MDA/VLDA). It isimportant to note that response rates based on the more stringent of thecriteria, e.g., VLDA, PASDAS very low disease activity, and DAPSAremission, were further improved beyond Week24 in patients who continuedto receive guselkumab (FIGS. 5A-J).

Based on SMD, ES, and SRM, the PASDAS and AMDF-based GRACE indicesappear to be more sensitive than the mCPDAI and DAPSA indices indetecting changes in disease activity afforded by guselkumab treatmentand distinguishing these effects from those of placebo. Consistently, aprevious analysis utilizing data from the golimumab GO-REVEAL trial inPsA indicated that PASDAS and AMDF demonstrated larger effect sizes thanmCPDAI and DAPSA (Helliwel12014). The PASDAS is a weighted measureencompassing a wider spectrum of disease manifestations than, forexample, the largely articular DAPSA, and this may account for itslarger effect size. The PASDAS was also derived from real patient datausing regression analyses, and such methodology is likely to result onmore emphasis (weights) being given to domains that show the greatestchanges. Both the GRACE and CPDAI are modular measures and, despitecovering many important domains, their modular construction may inhibittheir responsiveness. It should also be remembered that most patients inthis study had polyarticular disease and were treated with a drug thathas demonstrated high levels of clinical efficacy; in othercircumstances the relative performance of these composite indices may bedifferent.

In terms of residual disease activity, >70% of patients who achievedlow, very low, or remitted disease activity based on PASDAS, GRACE,mCPDAI, DAPSA, and MDA/VLDA indices after guselkumab treatmentdemonstrated little residual skin disease, enthesitis, dactylitis, ortender joints. Consistent results were obtained in previousdeterminations based on the golimumab GO-REVEAL trial (Helliwell 2014).However, SJC>1 was observed in more than a third of patients achievingPASDAS very low disease activity, DAPSA remission, or MDA and in amajority of patients achieving PASDAS, GRACE, mCPDAI and DAPSA lowdisease activity. Further, despite achieving remission/low diseaseactivity states, most of these patients still had elevated CRP levels,indicating incomplete resolution of chronic inflammation. Clearly, noneof these composite minimal targets represent total abrogation of diseaseactivity.

Among all composite indices evaluated, VLDA appears to represent themost stringent (achieved by only 13.1% of guselkumab-treated patients atWeek44). Achievement of VLDA, however, resulted in the least amountresidual disease activity across all aspects of disease evaluated otherthan CRP. While the small number of patients achieving VLDA in thisstudy should be noted, consistent results were recently reported basedon a retrospective analysis of 347 patients who received standard orbiological DMARDS in either the Tight Control of PsA (TICOPA) study oran observational cohort study (Coates L C et al, Arthritis Rheumatol2018, 70:345-355). Herein, all patients achieving PASDAS very lowdisease activity and 20/22 (90.9%) achieving DAPSA remission alsoachieved MDA, while 15/23 (65.2%) patients who met the MDA criteria didnot achieve PASDAS very low disease activity and 13/23 (56.5%) did notmeet the DAPSA remission criteria, suggesting PASDAS very low diseaseactivity and DAPSA remission criteria are more stringent and difficultto achieve than MDA.

Future challenges for composite measures will be to strike the correctbalance between comprehensiveness and feasibility, particularly in theclinic. Composite indices such as the PASDAS and GRACE are complex andtime consuming to fulfill, yet it could be argued that completeevaluation of any patient with PsA requires assessment of all clinicaldomains. If it is worth collecting the additional data for some of thesecomposite indices, then we need to be clear about the benefit. In theclinic, ‘simply’ collecting the data required for the DAPSA willencourage incomplete assessment and could give a false impression ofoverall disease activity. Should the new composite indices only be usedin clinical trials? Currently, the answer is in the affirmative (Coates2018a), but with further use and evolution, it is possible that a‘short-hand’ version can be developed for clinic use. Outside ofdedicated centers, the use of composite measures might be limited tothose patients exhibiting more complex clinical manifestations, whilethose with “oligosymptomatic” manifestations might readily be managedusing conventional tools.

Regarding limitations, the current analyses are hampered by the smallsize of the Phase 2 trial from which the data derive. Additionally, theSF-36 PCS score is a component of PASDAS, and thus was not anindependent measure in PASDAS validation. The evaluation of residualdisease is also limited by the small number of patients achievinglow/very low/remitted disease activity.

In conclusion, regardless of the PsA-specific composite index employed,guselkumab significantly improved disease activity through Week24;efficacy was well-maintained through Week44. Consistent with resultspreviously reported (Deodhar A et al, Lancet. 2018, 391:2213-24), thesefindings suggest guselkumab effectively treats diverse clinicalpresentations of PsA and achieves clinically meaningful therapeutictargets such as low/minimal disease activity or remission. The compositescores assessed are not uniform in either their responses or the diseasedomains included, indicating that choice of composite score in clinicaltrials and in clinic requires careful consideration to optimizefeasibility and performance.

Abbreviations and Acronyms

AE adverse eventBCC basal cell carcinomaBMI body mass indexBSA body surface area

DLQI Dermatology Life Quality Index

f-PGA Fingernail Physician's Global Assessmenthf-PGA Physician's Global Assessment of Hands and/or FeetHRQoL health-related quality of life

IGA Investigator's Global Assessment

IL interleukin

NAPSI Nail Psoriasis Area and Severity Index

NMSC nonmelanoma skin cancer

PASI Psoriasis Area and Severity Index

PRO patient-reported outcome

PSSD Psoriasis Sign and Symptom Diary

SAE serious adverse eventss-IGA Scalp-Specific Investigator's Global AssessmentTNFα-inhibitor tumor necrosis factor-α inhibitor

TABLES

TABLE 1 Summary of baseline patient characteristics (FAS) GuselkumabPlacebo 100 mg Total Number of patients 49 100 149 Age (years) 44.2(12.43) 47.4 (12.83) 46.3 (12.75) Male, n (%) 24 (49.0) 52 (52.0) 76(51.0) White, n (%) 49 (100) 100 (100) 149 (100) Body weight (kg) 86.3(20.52) 84.4 (21.41) 85.0 (21.07) PsA duration (years) 6.87 (7.24) 6.98(7.23) 6.94 (7.21) No. of swollen joints (0-66) 10.6 (7.51) 11.9 (7.60)11.5 (7.57) No. of tender joints (0-68) 20.1 (12.45) 20.7 (12.16) 20.5(12.22) Patient's assessment of pain (0-100 mm VAS) 61.9 (20.15) 62.1(21.53) 62.0 (21.01) Patient's global assessment of 64.7 (20.09) 67.0(20.63) 66.2 (20.41) disease activity (arthritis, 0-100 mm VAS)Physician's global assessment of 61.9 (15.86) 63.2 (16.76) 62.8 (16.43)disease activity (0-100 mm VAS) HAQ-DI score (0-3) 1.34 (0.54) 1.42(0.62) 1.39 (0.60) CRP (mg/dL), median (IQR) 0.9 (0.4, 2.0) 0.9 (0.5,1.8) 0.9 (0.4, 1.9) BSA, n (%) 13.6 (12.53) 17.2 (15.57) 16.0 (14.70)PASI score (0-72)^(a) 9.9 (7.98) 12.0 (10.52) 11.3 (9.78) Patients withenthesitis (per LEI), n (%) 31 (63.3) 76 (76.0) 107 (71.8) Enthesitisscore (1-6)^(b) 2.6 (1.48) 2.7 (1.54) 2.7 (1.52) Patients withdactylitis, n (%) 23 (46.9) 58 (58.0) 81 (54.4) Dactylitis score(1-60)^(c) 3.9 (3.01) 6.5 (6.15) 5.7 (5.55) SF-36 PCS score 34.4 (8.01)33.5 (7.09) 33.8 (7.39) MCS score 46.0 (12.52) 43.3 (11.48) 44.2 (11.86)Patients with prior use of, n (%) Anti-TNFα agent 4 (8.2) 9 (9.0) 13(8.7) DMARDs 41 (83.7) 90 (90.0) 131 (87.9) Patients receiving atbaseline, n (%) Methotrexate 19 (38.8) 47 (47.0) 66 (44.3) Dose(mg/week) 16.1 (3.57) 15.1 (4.20) 15.4 (4.03) Oral corticosteroids 8(16.3) 12 (12.0) 20 (13.4) Dose equivalent to prednisone (mg/day) 5.9(1.86) 7.8 (2.57) 7.0 (2.44) NSAIDs 36 (73.5) 70 (70.0) 106 (71.1) Datapresented are mean (SD) unless noted otherwise. ^(a)Among 146 patientswith PASI measurements at baseline (placebo, n = 48; guselkumab, n = 98)^(b)Among 107 patients with enthesitis at baseline (placebo, n = 31;guselkumab, n = 76) ^(c)Among 81 patients with dactylitis at baseline(placebo, n = 23; guselkumab, n = 58) BSA—body surface area,CRP—C-reactive protein, DMARDs—disease-modifying antirheumatic drugs,FAS—full analysis set (randomized and treated patients), HAQ-DI—HealthAssessment Questionnaire- Disability Index, IQR—interquartile range,LEI—Leeds Enthesitis Index, MCS—mental component summary,NSAIDs—nonsteroidal anti-inflammatory drugs, PASI—Psoriasis Area andSeverity Index, PCS—physical component summary, PsA—psoriatic arthritis,SD—standard deviation, SF-36—36-item Short-Form, TNF—tumor necrosisfactor, VAS—visual analog scale

TABLE 2 Summary of efficacy findings at Week 24 (mITT/FAS^(a)) EfficacyEndpoint Placebo Guselkumab p value Number of patients 49 100  ACR20, n(%) - Primary endpoint 9 (18.4) 58 (58.0) <0.001^(b) % difference^(b)(95% CI^(c)) 39.7 (25.3, 54.1) Risk Ratio (95% CI^(c)) 3.2 (1.7, 5.9)ACR20 with MTX at baseline 5/19 (26.3) 27/47 (57.4) ACR20 without MTX atbaseline 4/30 (13.3) 31/53 (58.5) ACR20 with prior anti-TNFα exposure0/4 (0) 6/9 (66.7) ACR20 without prior anti-TNFα exposure 9/45 (20.0)52/91 (57.1) ACR50, n (%) 5 (10.2) 34 (34.0) 0.002^(b) % difference^(b)(95% CI^(c)) 23.8 (11.3, 36.3) ACR70, n (%) 1 (2.0) 14 (14.0)0.023^(b,d) % difference^(b) (95% CI^(c)) 12.0 (4.2, 19.9) PASI75 -Major secondary endpoint 6/48 (12.5) 77/98 (78.6) <0.001^(b) %difference^(b) (95% CI^(c)) 66.1 (53.8, 78.4) PASI90 3/48 (6.3) 65/98(66.3) <0.001^(b) % difference^(b) (95% CI^(c)) 60.4 (48.9, 71.9)PASI100 3/48 (6.3) 39/98 (39.8) <0.001^(b) % difference^(b) (95% CI^(c))33.6 (21.7, 45.4) HAQ-DI, mean (SD) change from baseline - −0.06 (0.530)−0.42 (0.512) <0.001^(e) Major secondary endpoint LSMean difference(SE)^(e) −0.31 (0.082) (95% CI^(e)) (−0.471, −0.148) HAQ-DI responders(≥0.3 improvement³¹ 14 (28.6) 51 (51.0) 0.011^(b) from baseline), n (%)% difference^(b) (95% CI^(c)) 22.2 (6.2, 38.1) HAQ-DI responders (≥0.35improvement³² 14 (28.6) 51 (51.0) 0.011^(b,d) from baseline), n (%) %difference^(b) (95% CI^(c)) 22.2 (6.2, 38.1) Patients with enthesitis atbaseline 31 76 Median (IQR) % change from baseline- −33.33 (−100.0, 0.0)−100.00 (−100.0, −10.0) 0.009^(f) Major secondary endpoint Resolvedenthesitis, n (%) 9 (29.0) 43 (56.6) 0.012^(b) % difference^(b) (95%CI^(c)) 26.7 (7.2, 46.1) Patients with dactylitis at baseline 23 58Median (IQR) % change from baseline - −33.33 (−66.7, 0.0) −100.00(−100.0, −50.0) <0.001^(f) Major secondary endpoint Resolved dactylitis,n (%) 4 (17.4) 32 (55.2) 0.001^(b) % difference^(b) (95% CI^(c)) 39.3(19.4, 59.2) SF-36, mean (SD) change from baseline PCS score 0.46(6.513) 6.59 (7.465) <0.001^(g) Difference (95% CI)^(g) 6.1 (3.7, 8.6)MCS score 0.42 (6.737) 4.95 (9.064) 0.002^(g) Difference (95% CI)^(g)4.5 (1.6, 7.4) MDA^(h) achievement, n (%) 1 (2.0) 23 (23.0) 0.001^(b) %difference^(b) (95% CI^(c)) 21.2 (12.0, 30.3) VLDA^(i) achievement, n(%) 0 (0.0) 6 (6.0) 0.08^(b) % difference^(b) (95% CI^(c)) 6.1 (1.4,10.8) ^(a)Randomised patients who received ≥1 administration ofguselkumab or placebo and were analyzed per their assigned treatmentgroup regardless of actual treatment received. Patients who mettreatment-failure criteria, early escaped, or had missing data(including missing baseline) were considered nonresponders for ACR/MDAresponse endpoints at and after treatment failure/early escape. Forcontinuous endpoints, patients with missing baseline values wereexcluded; LOCF methodology was employed to impute post-baseline missingdata. For patients who early escaped, data following early escape wereconsidered as missing and were imputed using LOCF methods. ^(b)%differences and P values are based on the CMH test. ^(c)CIs are based onthe Wald statistic. ^(d)Derived from post-hoc analysis. ^(e)Statisticsare based on the MMRM analysis with treatment group, prior anti-TNF use,baseline HAQ-DI score, baseline MTX use (Yes, No), visit week, and aninteraction of treatment and visit week as the independent variables inthe model. ^(f)P values are based on the Wilcoxon rank sum test.^(g)Differences, CIs, and P values derived from an ANOVA. ^(h)Patient’sglobal assessment of disease activity on arthritis and psoriasis VASscore was used as one of the seven outcome measures to derive MDA.^(i)Post-hoc analysis. ACR20/50/70—American College of Rheumatology20/50/70% improvement, ANOVA—analysis of variance, CI—confidenceinterval, CMH—Cochran-Mantel-Haenszel, FAS—full analysis set,HAQ-DI—Health Assessment Questionnaire-Disability Index, LEI—LeedsEnthesitis Index, LOCF—last observation carried forward, LS—leastsquares, MCS—mental component summary, MDA—minimal disease activity,mITT—modified intent-to-treat, MMRM—mixed model for repeated measures,MTX—methotrexate, PASI50/75/90/100—Psoriasis Area and Severity Index50/75/90/100% improvement, PCS—physical component summary, SD—standarddeviation, SE—standard error, SF-36—36-item Short Form, TNF—tumornecrosis factor, VLDA—very low disease activity

TABLE 3 Summary of safety results through Week 24 and Week 56 (SAS)Through Week 56 Placebo/ Through Week 24 Guselkumab→ (Placebo-controlledperiod) Placebo→ Guselkumab Placebo→ Ustekinumab Placebo^(a)Guselkumab^(b) Guselkumab^(c) Guselkumab^(d) Combined Ustekinumab^(e)Combined Number of 49 100 29 100 129 17 10 27 patients Mean length of21.0 23.3 31.3 50.5 46.2 38.1 37.9 38.0 follow up (weeks) Mean number of3.6 3.9 3.9 6.4 5.8 3.8 3.9 3.9 administrations Patients with 16 (32.7)36 (36.0) 5 (17.2) 46 (46.0) 51 (39.5) 8 (47.1) 3 (30.0) 11 (40.7) 1 ormore AE(s), n (%) With MTX at 6/19 (31.6) 18/47 (38.3) 2/12 (16.7) 23/47(48.9) 25/59 (42.4) 2/7 (28.6) 1/3 (33.3) 3/10 (30.0) baseline No MTX at10/30 (33.3) 18/53 (34.0) 3/17 (17.6) 23/53 (43.4) 26/70 (37.1) 6/10(60.0) 2/7 (28.6) 8/17 (47.1) baseline Common AEs (>2% ofguselkumab-treated patients through Week 56) Elevated 1 (2.0) 4 (4.0) 2(6.9) 9 (9.0) 11 (8.5)^(g) 0 1 (10.0) 1 (3.7) transaminases^(f)Nasopharyngitis 5 (10.2) 6 (6.0) 0 10 (10.0) 10 (7.8) 2 (11.8) 0 2 (7.4)Leukopenia/ 0 5 (5.0) 1 (3.4) 6 (6.0) 7 (5.4)^(h) 0 0 0 WBC countdecreased Neutropenia/ 0 5 (5.0)^(i) 0 5 (5.0) 5 (3.9)^(i,j) 0 0 0neutrophil count decreased Upper 1 (2.0) 1 (1.0) 1 (3.4) 3 (3.0) 4 (3.1)0 0 0 respiratory tract infection Hepatic 0 1 (1.0) 0 3 (3.0) 3 (2.3) 00 0 steatosis Patients with 1 (2.0) 1 (1.0) 0 6 (6.0) 6 (4.7) 0 0 0 1 ormore SAE(s), n (%) Joint (knee) 1 (2.0) 0 0 0 0 0 0 0 injury Myocardial0 1 (1.0) 0 1 (1.0) 1 (0.8) 0 0 0 infarction Osteoarthritis 0 0 0 1(1.0) 1 (0.8) 0 0 0 Pneumonia 0 0 0 1 (1.0) 1 (0.8) 0 0 0 Pupils unequal0 0 0 1 (1.0) 1 (0.8) 0 0 0 Radius fracture 0 0 0 1 (1.0) 1 (0.8) 0 0 0Ulcerative 0 0 0 1 (1.0) 1 (0.8) 0 0 0 keratitis Patients with 0 1 (1.0)0 2 (2.0)^(k) 2 (1.6)^(k) 0 1 (10.0)^(k) 1 (3.7)^(k) AE(s) resulting instudy drug d/c, n (%) Leukopenia 0 1 (1.0)^(l) 0 1 (1.0) 1 (0.8)^(l) 0 00 Neutropenia 0 1 (1.0)^(l) 0 1 (1.0) 1 (0.8)^(l) 0 0 0 Pneumonia 0 0 01 (1.0) 1 (0.8) 0 0 0 Osteoarthritis 0 0 0 0 0 0 1 (10.0) 1 (3.7)Patients with 10 (20.4) 16 (16.0) 1 (3.4) 26 (26.0) 27 (20.9) 5 (29.4) 05 (18.5) infections^(m), n (%) Serious infections 0 0 0 1 (1.0) 1 (0.8)0 0 0 Infections 7 (14.3) 10 (10.0) 0 16 (16.0) 16 (12.4) 2 (11.8) 0 2(7.4) treated with oral/parenteral antimicrobial agents^(n) Patientswith 1 (2.0) 0 0 0 0 0 0 0 injection-site reactions, n (%) ^(a)Includesall AEs in placebo patients from Week 0 through Week 24; AEs are onlycounted for the placebo period. ^(b)Includes all AEs in guselkumabpatients from Week 0 through Week 24 irrespective of early-escapestatus; AEs for patients who early escaped at Week 16 are only countedthrough Week 16. ^(c)Includes all AEs in placebo patients who crossedover to guselkumab from Week 24 through Week 56; ^(d)Includes all AEs inguselkumab patients from Week 0 through Week 56 irrespective of earlyescape, AEs for patients who early escaped are counted through Week 16.^(e)Includes all AEs in patients who early escaped from Week 16throughWeek 56. ^(f)Includes the following AE preferred terms: alanineaminotransferase increased, aspartate aminotransferase increased,hepatitis, liver function test abnormal, liver function test increased,and transaminases increased. ^(g)Six patients were taking concomitantMTX; three events were considered reasonably related to study treatmentby the investigator. ^(h)Four patients were taking concomitant MTX andthree without concomitant MTX. Among the seven patients with AEs ofleukopenia/WBC count decreased, two had the lowest leukocyte countsmeeting NCI CTCAE Grade 1 and five had leukocyte counts meeting CTCAEGrade 2 criteria. ^(i)Among the five patients with neutropenia, fourpatients also reported leukopenia/WBC count decreased and were includedin the seven patients who reported leukopenia/WBC count decreased. Onepatient had the lowest neutrophil counts meeting NCI CTCAE Grade 1,three met CTCAE Grade 2, and one met CTCAE Grade 3. ^(j)Three patientswere taking concomitant MTX and two patients were not taking concomitantMTX. ^(k)From Week 0 through Week 44 (final study agent injection).^(l)Leukopenia/neutropenia were reported by the same patient, with onsetprior to Week 24 and discontinuation after Week 24. ^(m)AEs identifiedby investigators as infections. ^(n)Including antibacterial, antifungal,and antiviral agents. AE—adverse event, d/c—discontinuation,MTX—methotrexate, SAE—serious adverse event, SAS—safety analysis set(treated patients), WBC—white blood cell

TABLE S1 Summary of primary endpoint (ACR20 response at week 24) -sensitivity analysis Placebo Guselkumab p value^(a) Full analysis set 49100 Mean ACR20 response - Bayesian 18.8 58.0 analysis^(b), % %difference (95% Credible Interval^(c)) 39.2 (25.4, 52.4) Probability^(c)of difference >0 100 Probability^(c) of difference >20% 99.6 ACR20response - Without treatment- 9 (18.4) 58 (58.0) <0.001 failurerules^(d), n (%) % difference^(a) (95% CI^(e)) 39.7 (25.3, 54.1) ACR20response - Observed data^(f), n/N (%) 11/46 (23.9) 59/97 (60.8) <0.001 %difference^(a) (95% CI^(e)) 36.9 (21.4, 52.5) ACR20 response - Excludingpatients 9/46 (19.6) 58/97 (59.8) <0.001 with all ACR components missingat Week 24^(g), n/N (%) % difference^(a) (95% CI^(e)) 40.2 (25.3, 55.2)ACR20 response based on IPW estimates^(h), 9 (18.5) 58 (58.2) n (%) %difference (95% CI^(i)) 39.7 (16.1, 61.1) ACR20 response in per-protocolset^(j) 9/29 (31.0) 57/86 (66.3) 0.0010 ^(a)Differences and P values arebased on the CMH test unless otherwise specified. ^(b)The mean responseis the mean of the posterior distribution of placebo and guselkumabgroups, respectively. ^(c)95% credible interval and probabilities arecalculated using simulations from the posterior distributions of placeboand guselkumab groups. ^(d)ACR20 response is based on imputed valueswith early escape and missing data rules applied; no treatment failurerules were applied. ^(e)The CIs are based on the Wald statistic.^(f)ACR20 response is based on observed values without any data handlingrules applied. ^(g)ACR20 response is based on imputed values withtreatment failure, early escape and missing data rules applied, butexcluding patients who had all ACR components missing at Week 24.^(h)ACR20 response is based on IPW estimates without data handling rulesapplied. Efficacy measurements after early escape or treatment failurewere set to missing, and the inclusion probabilities of non-missing datawere estimated using a logistic regression model that includedcovariates of baseline characteristics, treatment assignment, and thelast efficacy measurement before the missing value(s). ^(i)The CI isbased on the 2.5th and 97.5th percentiles from the bootstrap sampledistribution of treatment difference. ^(j)Per-protocol set includes allrandomized patients who completed the Week-24 visit and did notdiscontinue study agent administration prior to or at Week 24 and didnot early escape at Week 16. ACR20—American College of Rheumatology 20%improvement, CI—confidence interval, CMH—Cochran-Mantel-Haenszel,FAS—full analysis set, IPW—Inverse Probability Weighting

TABLE S2 Summary of ACR responses at Week 16, Week 24, Week 44, and Week56 in patients who early escaped to ustekinumab at Week 16 based onobserved data in the ustekinumab populations. Data presented are n (%).Placebo→ Ustekinumab Guselkumab→ Ustekinumab Week 16 Week 24 Week 44Week 56 Week 16 Week 24 Week 44 Week 56 N 17 17 16 15 10 10 10 8 ACR20 0(0.0)  2 (11.8) 8 (50.0) 5 (33.3) 0 (0.0)  1 (10.0) 5 (50.0) 5 (62.5)ACR50 0 (0.0) 1 (5.9) 5 (31.3) 4 (26.7) 0 (0.0) 0 (0.0) 3 (30.0) 1(12.5) ACR70 0 (0.0) 1 (5.9) 2 (12.5) 3 (20.0) 0 (0.0) 0 (0.0) 1 (10.0)1 (12.5) ACR20/50/70—American College of Rheumatology 20/50/70%improvement

TABLE S3 Summary of efficacy results from Week 24 through Week 44 andWeek 56 based on observed data in the post-Week 24 efficacy analysisset. Data presented are n (%) unless noted otherwise. Placebo→Guselkumab^(a) Guselkumab^(b) Efficacy Endpoint Week 24 Week 44 Week 56Week 24 Week 44 Week 56 N^(c) 29 28 27 86 84 83 ACR20 9 (31.0) 21 (75.0)22 (81.5) 57 (66.3) 65 (77.4) 61 (73.5) ACR50 5 (17.2) 13 (46.4) 18(66.7) 34 (39.5) 39 (46.4) 44 (53.0) ACR70 1 (3.4) 7 (25.0) 8/28 (28.6)14 (16.3) 22 (26.2) 27 (32.5) N^(c) 29 28 27 86 83 82 PASI75 6 (20.7) 23(82.1) 22 (81.5) 71 (82.6) 75 (90.4) 70 (85.4) PASI90 3 (10.3) 21 (75.0)20 (74.1) 61 (70.9) 68 (81.9) 64 (78.0) PASI100 3 (10.3) 19 (67.9) 15(55.6) 38 (44.2) 53 (63.9) 47 (57.3) N^(c) 29 28 28 86 84 83 Mean (SD)change from baseline −0.19 (0.581) −0.63 (0.612) −0.67 (0.558) −0.46(0.530) −0.54 (0.598) −0.55 (0.621) in HAQ-DI HAQ-DI responders (≥0.30)13 (44.8) 20 (71.4) 21 (75.0) 48 (55.8) 52 (61.9) 49 (59.0) HAQ-DIresponders (≥0.35) 13 (44.8) 20 (71.4) 21 (75.0) 48 (55.8) 52 (61.9) 49(59.0) Patients with baseline enthesitis, N 18 17 16 67 66 65 Median(IQR) % change from −50.0 −100.0 −100.0 −100.0 −100.0 −100.0 baseline inLEI (−100.0, 0.0) (−100.0, −60.0)  (−100.0, −35.0)  (−100.0, −50.0)(−100.0, −50.0)  (−100.0, −50.0) Enthesitis resolved, n (%) 6 (33.3) 9(52.9) 10 (62.5) 41 (61.2) 41 (62.1) 46 (70.8) Patients with baselinedactylitis, N 16 16 16 50 49 48 Median (IQR) % change from −45.0 −100.0−100.0 −100.0 −100.0 −100.0 baseline in dactylitis score  (−70.8, 0.0)(−100.0, −100.0) (−100.0, −100.0) (−100.0, −80.0) (−100.0, −100.0)(−100.0, −95.0) Dactylitis resolved, n (%) 3 (18.8) 14 (87.5) 15 (93.8)30 (60.0) 39 (79.6) 36 (75.0) SF-36, mean (SD) change from 28 28 n/a 8684 n/a baseline, N PCS score 2.13 (7.365) 8.02 (8.647) n/a 7.40 (7.448)8.34 (8.783) n/a MCS score 0.51 (6.770) 5.53 (9.013) n/a 5.45 (9.081)4.56 (9.548) n/a MDA^(d) achievement, n/N (%) 1/29 (3.4) 8/28 (28.6) n/a23/86 (26.7) 29/84 (34.5) n/a VLDA^(d) achievement, n/N (%) 0/29 (0.0)4/28 (14.3) n/a 6/86 7.0) 11/84 (13.1) n/a ^(a)Includes the placebopatients who crossed over to receive guselkumab at Week 24. Data at Week24 represent the last assessments prior to receiving guselkumab.^(b)Includes the patients in the guselkumab group who did not earlyescape at Week 16 and did not discontinue study treatment prior to or atWeek 24. ^(c)Unless noted otherwise. ^(d)Patient’s global assessment ofdisease activity on arthritis and psoriasis VAS score was used as one ofthe seven outcome measures to derive MDA or VLDA. ACR20/50/70—AmericanCollege of Rheumatology 20/50/70% improvement, HAQ-DI—Health AssessmentQuestionnaire-Disability Index, IQR—interquartile range, MCS—mentalcomponent summary, MDA—minimal disease activity, n/a—not assessed,PASI50/75/90/100—Psoriasis Area and Severity Index 50/75/90/100%improvement, PCS—physical component summary, SD—standard deviation,SF-36—36-item Short Form, VLDA—very low disease activity

TABLE S4 Number (%) of patients meeting residual disease activitycriteria among guselkumab-treated patients achieving low diseaseactivity states defined by PsA composite indices at Week 24 (fullanalysis set;)* Measure of residual disease activity PASI ≤ 1 TJC ≤ 1SJC ≤ 1 CRP ≤ ULN LEI = 0 Dactylitis = 0 MDA VLDA PASDAS Very low(≤1.9); 7 (87.5) 8 (100.0) 5 (62.5) 4 (50.0) 8 (100.0) 8 (100.0) 8(100.0) 3 (37.5) N = 8 Low (>1.9-≤3.2), 22/26 (84.6) 20 (74.1) 12 (44.4)12 (44.4) 23 (85.2) 25 (92.6) 12 (48.0) 3 (12.0) N = 27 GRACE Low(≤2.3), N = 29 26 (89.7) 23 (79.3) 14 (48.3) 9 (31.0) 24 (82.8) 27(93.1) 21 (75.0) 6 (21.4) mCPDAI Low (≤3.2), N = 50 40 (80.0) 38 (76.0)19 (38.0) 20 (40.0) 46 (92.0) 46 (92.0) 22 (44.9) 6 (12.2) DAPSARemission (≤4), 9 (75.0) 12 (100.0) 8 (66.7) 6 (50.0) 11 (91.7) 12(100.0) 10 (90.9) 4 (36.4) N = 12 Low (>4-≤14), 19/27 (70.4) 22 (78.6)10 (35.7) 11 (39.3) 22 (78.6) 22 (78.6) 12 (44.4) 2 (7.4) N = 28 MDA, N= 23 21 (91.3) 20 (87.0) 14 (60.9) 5 (21.7) 19 (82.6) 22 (95.7) — 6(26.1%) VLDA, N = 6 6 (100) 6 (100) 6 (100) 1 (16.7) 6 (100) 6 (100) 6(100) — *PsA = psoriatic arthritis, PASI = Psoriatic Area and SeverityIndex, TJC = tender joint count, SJC = swollen joint count, CRP =C-reactive protein, ULN = upper limit of normal (0.287 mg/dL), LEI =Leeds enthesitis index, MDA = minimal disease activity, VLDA = very lowdisease activity, PASDAS = Psoriatic ArthritiS Disease Activity Score,GRACE = Group for Research and Assessment of Psoriasis and PsoriaticArthritis (GRAppa) Composite scorE, mCPDAI = modified CompositePsoriatic Disease Activity Index, DAPSA = Disease Activity Index forPSoriatic Arthritis

TABLE S5 Change in Dactylitis Score in ACR20/50 and PASI75 Respondersand Non-responders Mean (SD) change from BL in Dactylitis Score at Wk 24Non-responders Responders p-value ACR 20 −1.76(7.595), n = 21−4.94(4.666), n = 36 0.044 ACR 50 −2.44(6.213), n = 36 −6.05(5.133), n =21 0.027 PASI 75 −4.00(2.858), n = 13 −3.70(6.736), n = 44 0.924

What is claimed:
 1. A method of treating psoriatic arthritis in apatient, comprising administering an antibody to IL-23 to the patient ina clinically proven safe and clinically proven effective amount, whereinthe antibody comprises a light chain variable region and a heavy chainvariable region, said light chain variable region comprising: acomplementarity determining region light chain 1 (CDRL1) amino acidsequence of SEQ ID NO:50; a CDRL2 amino acid sequence of SEQ ID NO:56;and a CDRL3 amino acid sequence of SEQ ID NO:73, said heavy chainvariable region comprising: a complementarity determining region heavychain 1 (CDRH1) amino acid sequence of SEQ ID NO:5; a CDRH2 amino acidsequence of SEQ ID NO:20; and a CDRH3 amino acid sequence of SEQ IDNO:44.
 2. The method of claim 1, wherein the antibody is administered inan initial subcutaneous dose at week 0, a subcutaneous dose at week 4and a subcutaneous dose every 8 weeks thereafter (q8w).
 3. The method ofclaim 2, wherein the antibody is administered at a dose of between 25 mgand 200 mg.
 4. The method of claim 2, wherein the antibody isadministered at a dose of 50 mg or 100 mg.
 5. The method of claim 2,wherein the antibody is administered at a dose of 100 mg.
 6. The methodof claim 5, wherein the patient is a responder to the treatment with theantibody and is identified as having a statistically significantimprovement in disease activity as determined by the American College ofRheumatology 20% improvement criteria (ACR20) by week 24 of treatmentwith the antibody.
 7. The method of claim 5, wherein the patient is aresponder to the treatment with the antibody and is identified as havinga statistically significant improvement in disease activity asdetermined by the American College of Rheumatology 20% improvementcriteria (ACR20) by week 16 of treatment with the antibody.
 8. Themethod of claim 5, wherein the patient is a responder to the treatmentwith the antibody and is identified as having a statisticallysignificant improvement in disease activity as determined by thePsoriasis Area and Severity Index 75, 90 and 100 (PASI75/90/100) by week24 of treatment with the antibody.
 9. The method of claim 5, wherein thepatient is a responder to the treatment with the antibody and isidentified as having a statistically significant improvement in diseaseactivity as determined by the American College of Rheumatology 50% and70% improvement criteria (ACR50/70) by week 24 of treatment with theantibody.
 10. The method of claim 5, wherein the patient is a responderto the treatment with the antibody and is identified as having astatistically significant improvement in disease activity as determinedby the Health Assessment Questionnaire Disability Index (HAQ-DI) by week24 of treatment with the antibody.
 11. The method of claim 5, whereinthe patient is a responder to the treatment with the antibody and isidentified as having statistically significant improvement in diseaseactivity as determined by the Leeds enthesitis index (LEI) by week 24 oftreatment with the antibody.
 12. The method of claim 5, wherein thepatient is a responder to the treatment with the antibody and isidentified as having statistically significant improvement in diseaseactivity as determined by the dactylitis assessment score of 0-3((0=absent, 1=mild, 2=moderate, 3=severe) by week 24 of treatment withthe antibody.
 13. The method of claim 5, wherein the patient is aresponder to the treatment with the antibody and is identified as havinga statistically significant improvement in disease activity asdetermined by the Short-Form 36 (SF-36) health survey by week 24 oftreatment with the antibody.
 14. The method of claim 5, wherein thepatient is a responder to the treatment with the antibody and isidentified as having a statistically significant improvement in diseaseactivity as determined by the mental and physical component summary (MCSand PCS) scores by week 24 of treatment with the antibody.
 15. Themethod of claim 5, wherein the patient is a responder to the treatmentwith the antibody and is identified as having a statisticallysignificant improvement in disease activity as determined the minimaldisease activity (MDA) criteria by week 24 of treatment with theantibody.
 16. The method of claim 5, wherein the patient is a responderto the treatment with the antibody and is identified as having astatistically significant improvement in disease activity as determinedthe Psoriatic ArthritiS Disease Activity Score (PASDAS) by week 24 oftreatment with the antibody.
 17. The method of claim 5, wherein thepatient is a responder to the treatment with the antibody and isidentified as having a statistically significant improvement in diseaseactivity as determined the GRAppa Composite scorE (GRACE) Index by week24 of treatment with the antibody.
 18. The method of claim 5, whereinthe patient is a responder to the treatment with the antibody and isidentified as having a statistically significant improvement in diseaseactivity as determined the modified Composite Psoriatic Disease ActivityIndex (mCPDAI) by week 24 of treatment with the antibody.
 19. The methodof claim 5, wherein the patient is a responder to the treatment with theantibody and is identified as having a statistically significantimprovement in disease activity as determined the Disease Activity Indexfor PSoriatic Arthritis (DAPSA) by week 24 of treatment with theantibody.
 20. The method of claim 5, wherein the patient is a responderto the treatment with the antibody and is identified as having astatistically significant improvement in disease activity as determinedthe Routine Assessment of Patient Index Data 3 (RAPID3) by week 24 oftreatment with the antibody.
 21. The method of claim 5, wherein thepatient is a responder to the treatment with the antibody and isidentified as having a statistically significant improvement in diseaseactivity by week 24 of treatment, wherein disease activity is determinedby one or more criteria selected from the group consisting of theAmerican College of Rheumatology 20% improvement criteria (ACR20), theAmerican College of Rheumatology 50% improvement criteria (ACR50), thePsoriasis Area and Severity Index 75, 90 and 100 (PASI75/90/100), theAmerican College of Rheumatology 50% and 70% improvement criteria(ACR50/70), the Health Assessment Questionnaire Disability Index(HAQ-DI), the Leeds enthesitis index (LEI), the dactylitis assessmentscore (0=absent, 1=mild, 2=moderate, 3=severe), changes in Short FormHealth survey (SF-36), changes in the mental and physical componentsummary (MCS and PCS), the achievement of minimal disease activity(MDA), the Psoriatic ArthritiS Disease Activity Score (PASDAS), theGRAppa Composite scorE (GRACE) Index, the modified Composite PsoriaticDisease Activity Index (mCPDAI), the Disease Activity Index forPSoriatic Arthritis (DAPSA), and the Routine Assessment of Patient IndexData 3 (RAPID3).
 22. The method of claim 5, wherein the ACR20, ACR50,ACR70, PASI70, PASI90, PSAI100, MDA, HAQ-DI, LEI/dactylitis, SF-36 PCS,PASDAS, GRACE, mCPDAI, DAPSA, RAPID3 or MCS score is measured 16, 20, 24or 28 weeks after initial treatment.
 23. The method of claim 5, whereinthe antibody is guselkumab administered subcutaneously.
 24. The methodof claim 23, wherein the antibody is in a composition comprising 100mg/mL of antibody; 7.9% (w/v) sucrose, 4.0 mM Histidine, 6.9 mML-Histidine monohydrochloride monohydrate; 0.053% (w/v) Polysorbate 80of the pharmaceutical composition; wherein the diluent is water atstandard state.
 25. The method of claim 1, further comprisingadministering to the patient one or more additional drugs used to treatpsoriasis arthritis.
 26. The method of claim 25, wherein the additionaldrug is selected from the group consisting of: immunosuppressive agents,non-steroidal anti-inflammatory drugs (NSAIDs), methotrexate (MTX),anti-B-cell surface marker antibodies, anti-CD20 antibodies, rituximab,TNF-inhibitors, corticosteroids, and co-stimulatory modifiers.
 27. Themethod of claim 1, wherein the antibody is effective to reduce a symptomof psoriatic arthritis in the patient, induce clinical response, induceor maintain clinical remission, inhibit disease progression, or inhibita disease complication in the patient.
 28. A method of treatingpsoriatic arthritis in a patient, comprising administering an antibodyto IL-23 to the patient in a safe and effective amount, wherein theantibody comprises a light chain variable region of the amino acidsequence of SEQ ID NO: 116 and a heavy chain variable region of theamino acid sequence of SEQ ID NO:
 106. 29. The method of claim 28,wherein the antibody is administered in an initial subcutaneous dose atweek 0, a subcutaneous dose at week 4 and a subcutaneous does every 8weeks thereafter (q8w).
 30. The method of claim 28, wherein the antibodyis administered at a dose of between 25 mg and 200 mg.
 31. The method ofclaim 28, wherein the antibody is administered at a dose of 50 mg or 100mg.
 32. The method of claim 28, wherein the antibody is administered ata dose of 100 mg.
 33. The method of claim 32, wherein the patient is aresponder to the treatment with the antibody and is identified as havinga statistically significant improvement in disease activity asdetermined by the American College of Rheumatology 20% improvementcriteria (ACR20) by week 24 of treatment with the antibody.
 34. Themethod of claim 32, wherein the patient is a responder to the treatmentwith the antibody and is identified as having a statisticallysignificant improvement in disease activity as determined by theAmerican College of Rheumatology 20% improvement criteria (ACR20) byweek 16 of treatment with the antibody.
 35. The method of claim 32,wherein the patient is a responder to the treatment with the antibodyand is identified as having a statistically significant improvement indisease activity as determined by the Psoriasis Area and Severity Index75, 90 and 100 (PASI75/90/100) by week 24 of treatment with theantibody.
 36. The method of claim 32, wherein the patient is a responderto the treatment with the antibody and is identified as having astatistically significant improvement in disease activity as determinedby the American College of Rheumatology 50% and 70% improvement criteria(ACR50/70) by week 24 of treatment with the antibody.
 37. The method ofclaim 32, wherein the patient is a responder to the treatment with theantibody and is identified as having a statistically significantimprovement in disease activity as determined by the Health AssessmentQuestionnaire Disability Index (HAQ-DI) by week 24 of treatment with theantibody.
 38. The method of claim 32, wherein the patient is a responderto the treatment with the antibody and is identified as havingstatistically significant improvement in disease activity as determinedby the Leeds enthesitis index (LEI) by week 24 of treatment with theantibody.
 39. The method of claim 32, wherein the patient is a responderto the treatment with the antibody and is identified as havingstatistically significant improvement in disease activity as determinedby the dactylitis assessment score of 0-3 ((0=absent, 1=mild,2=moderate, 3=severe) by week 24 of treatment with the antibody.
 40. Themethod of claim 32, wherein the patient is a responder to the treatmentwith the antibody and is identified as having a statisticallysignificant improvement in disease activity as determined by theShort-Form 36 (SF-36) health survey by week 24 of treatment with theantibody.
 41. The method of claim 32, wherein the patient is a responderto the treatment with the antibody and is identified as having astatistically significant improvement in disease activity as determinedby the mental and physical component summary (MCS and PCS) scores byweek 24 of treatment with the antibody.
 42. The method of claim 32,wherein the patient is a responder to the treatment with the antibodyand is identified as having a statistically significant improvement indisease activity as determined the minimal disease activity (MDA)criteria by week 24 of treatment with the antibody.
 43. The method ofclaim 32, wherein the patient is a responder to the treatment with theantibody and is identified as having a statistically significantimprovement in disease activity as determined the Psoriatic ArthritiSDisease Activity Score (PASDAS) by week 24 of treatment with theantibody.
 44. The method of claim 32, wherein the patient is a responderto the treatment with the antibody and is identified as having astatistically significant improvement in disease activity as determinedthe GRAppa Composite scorE (GRACE) Index by week 24 of treatment withthe antibody.
 45. The method of claim 32, wherein the patient is aresponder to the treatment with the antibody and is identified as havinga statistically significant improvement in disease activity asdetermined the modified Composite Psoriatic Disease Activity Index(mCPDAI) by week 24 of treatment with the antibody.
 46. The method ofclaim 32, wherein the patient is a responder to the treatment with theantibody and is identified as having a statistically significantimprovement in disease activity as determined the Disease Activity Indexfor PSoriatic Arthritis (DAPSA) by week 24 of treatment with theantibody.
 47. The method of claim 32, wherein the patient is a responderto the treatment with the antibody and is identified as having astatistically significant improvement in disease activity as determinedthe Routine Assessment of Patient Index Data 3 (RAPID3) by week 24 oftreatment with the antibody.
 48. The method of claim 32, wherein thepatient is a responder to the treatment with the antibody and isidentified as having a statistically significant improvement in diseaseactivity by week 24 of treatment, wherein disease activity is determinedby one or more criteria selected from the group consisting of theAmerican College of Rheumatology 20% improvement criteria (ACR20), theAmerican College of Rheumatology 50% improvement criteria (ACR50), thePsoriasis Area and Severity Index 75, 90 and 100 (PASI75/90/100), theAmerican College of Rheumatology 50% and 70% improvement criteria(ACR50/70), the Health Assessment Questionnaire Disability Index(HAQ-DI), the Leeds enthesitis index (LEI), the dactylitis assessmentscore (0=absent, 1=mild, 2=moderate, 3=severe), changes in Short FormHealth survey (SF-36), changes in the mental and physical componentsummary (MCS and PCS), the achievement of minimal disease activity(MDA), the Psoriatic ArthritiS Disease Activity Score (PASDAS), theGRAppa Composite scorE (GRACE) Index, the modified Composite PsoriaticDisease Activity Index (mCPDAI), the Disease Activity Index forPSoriatic Arthritis (DAPSA), and the Routine Assessment of Patient IndexData 3 (RAPID3).
 49. The method of claim 32, wherein the ACR20, ACR50,ACR70, PASI70, PASI90, PSAI100, MDA, HAQ-DI, LEI/dactylitis, SF-36 PCS,PASDAS, GRACE, mCPDAI, DAPSA, RAPID3 or MCS score is measured 16, 20, 24or 28 weeks after initial treatment.
 50. The method of claim 32, whereinthe antibody is guselkumab administered subcutaneously.
 51. The methodof claim 50, wherein the antibody is in a composition comprising 100mg/mL of antibody; 7.9% (w/v) sucrose, 4.0 mM Histidine, 6.9 mML-Histidine monohydrochloride monohydrate; 0.053% (w/v) Polysorbate 80of the pharmaceutical composition; wherein the diluent is water atstandard state.
 52. The method of claim 28, further comprisingadministering to the patient one or more additional drugs used to treatpsoriasis arthritis.
 53. The method of claim 52, wherein the additionaldrug is selected from the group consisting of: immunosuppressive agents,non-steroidal anti-inflammatory drugs (NSAIDs), methotrexate (MTX),anti-B-cell surface marker antibodies, anti-CD20 antibodies, rituximab,TNF-inhibitors, corticosteroids, and co-stimulatory modifiers.
 54. Themethod of claim 28, wherein the antibody is effective to reduce asymptom of psoriatic arthritis in the patient, induce clinical response,induce or maintain clinical remission, inhibit disease progression, orinhibit a disease complication in the patient.
 55. A method of treatingpsoriatic arthritis in a patient that is a non-responder to a TNFinhibitors, comprising administering an antibody to IL-23 to the patientin a clinically proven safe and clinically proven effective amount,wherein the antibody comprises a light chain variable region and a heavychain variable region, said light chain variable region comprising: acomplementarity determining region light chain 1 (CDRL1) amino acidsequence of SEQ ID NO:50; a CDRL2 amino acid sequence of SEQ ID NO:56;and a CDRL3 amino acid sequence of SEQ ID NO:73, said heavy chainvariable region comprising: a complementarity determining region heavychain 1 (CDRH1) amino acid sequence of SEQ ID NO:5; a CDRH2 amino acidsequence of SEQ ID NO:20; and a CDRH3 amino acid sequence of SEQ IDNO:44.
 56. The method of claim 55, wherein the TNF inhibitor isadalilumab or eternacept.
 57. The method of claim 56, wherein thepatient is determined to be a non-responder to a TNF inhibitors bymeasuring the PASI70/90/100 and/or ACR20/50/70 score.
 58. A method oftreating psoriatic arthritis in a patient that is a non-responder to aTNF inhibitors, comprising administering an antibody to IL-23 to thepatient in a clinically proven safe and clinically proven effectiveamount, wherein the antibody comprises a light chain variable region ofthe amino acid sequence of SEQ ID NO: 116 and a heavy chain variableregion of the amino acid sequence of SEQ ID NO:
 106. 59. The method ofclaim 58, wherein the TNF inhibitor is adalilumab or eternacept.
 60. Themethod of claim 59, wherein the patient is determined to be anon-responder to a TNF inhibitors by measuring the PASI70/90/100 and/orACR20/50/70 score.
 61. A method of treating moderate-to-severe psoriaticarthritis in adult patients who are candidates for systemic therapy orphototherapy, comprising administering an antibody to IL-23 to thepatient in a clinically proven safe and clinically proven effectiveamount, wherein the antibody comprises a complementarity determiningregion light chain 1 (CDRL1) amino acid sequence of SEQ ID NO:50; aCDRL2 amino acid sequence of SEQ ID NO:56; a CDRL3 amino acid sequenceof SEQ ID NO:73; a complementarity determining region heavy chain 1(CDRH1) amino acid sequence of SEQ ID NO:5; a CDRH2 amino acid sequenceof SEQ ID NO:20; and a CDRH3 amino acid sequence of SEQ ID NO:44, thedosage is 100 mg administered by subcutaneous injection at Week 0, Week4 and every 8 weeks thereafter and the antibody is at a concentration of100 mg/mL in a single-dose prefilled syringe comprising 7.9% (w/v)sucrose, 4.0 mM Histidine, 6.9 mM L-Histidine monohydrochloridemonohydrate; 0.053% (w/v) Polysorbate 80 and the diluent is water atstandard state.
 62. A method of treating moderate-to-severe psoriaticarthritis in adult patients who are candidates for systemic therapy orphototherapy, comprising administering an antibody to IL-23 to thepatient in a clinically proven safe and clinically proven effectiveamount, wherein the antibody comprises a light chain variable region ofthe amino acid sequence of SEQ ID NO: 116 and a heavy chain variableregion of the amino acid sequence of SEQ ID NO: 106, the dosage is 100mg administered by subcutaneous injection at Week 0, Week 4 and every 8weeks thereafter and the antibody is at a concentration of 100 mg/mL ina single-dose prefilled syringe comprising 7.9% (w/v) sucrose, 4.0 mMHistidine, 6.9 mM L-Histidine monohydrochloride monohydrate; 0.053%(w/v) Polysorbate 80 and the diluent is water at standard state.